Screening method

ABSTRACT

The invention relates to a method for identification of substances which are applicable for treatment or prevention of an insufficient longitudinal growth of the eye (hypermetropia) or for treatment or prevention of an excessive longitudinal growth of the eye (myopia); substances identified by the method for treating or preventing conditions related to the longitudinal growth of the eye; substances and mixtures of substances for the preparation of a pharmaceutical composition for the treatment or prevention of abnormal growth of the axial length of the eye. The identification involves measuring the effect of the substances on the retinal pigment epithelium of the eye, e.g. by detecting the metabolic effect of the substance on the retinal epithelium, the effect on the standing potential or the effect on the proteoglycanes of the scleral tissue of the eye, by way of EOG examination, by way on the size of the so-called c-wave in ERG-recordings, or by the state of the Ca 2+ -channels or on the [ 3 H]-ryanodine receptors of the retinal pigment epithelium.

[0001] The invention relates to a method for identification ofsubstances which are applicable for treatment or prevention of aninsufficient longitudinal growth of the eye (hypermetropia) or fortreatment or prevention of an excessive longitudinal growth of the eye(myopia); substances identified by the method for treating or preventingconditions related to the longitudinal growth of the eye; substances andmixtures of substances for the preparation of a pharmaceuticalcomposition for the treatment or prevention of abnormal growth of theaxial length of the eye.

BACKGROUND OF THE INVENTION

[0002] Myopia is caused by the length of the eye being too big inrelation to the optical strength of the cornea and the lens so that thepicture of a distant object is focused in a point in front of theretina, whereas the picture produced on the retina will be blurred. Inother words, myopia is caused by an anomaly between the length of theeye (the axial length) and the refraction in the cornea and the lens.

[0003] The longitudinal growth of the eye (from approximately 17 mm atbirth to approximately 24 mm) during the childhood is caused byexpansion of the eye content and thus stretching the immature connectivetissue in the sclera of the eye which adjusts to the new size of theeye. Normally the eye will reach its permanent length at the age of 12,at which time the connective tissue in the sclera reaches an appropriatedegree of maturity and the longitudinal growth of the eye will stop.

[0004] In myopic persons the longitudinal growth of the eye is too highand the longitudinal growth of the eye continues for a longer period oftime than in normal individuals.

[0005] Hypermetropia is caused by the length of the eye being too shortin relation to the optical strength of the cornea and the lens.Hypermetropia usually prevails at birth and is normally recorded at theage of 3-5 years. Subsequently it will reduce in proportion with thegrowth of the eye until the age of 12, from which age it will remainconstant for the rest of the persons life.

[0006] Approximately 25% of the population are myopic. In some myopicpersons the axial length is normal (physiological myopia of <−4dioptry), in other parsons, the axial length grow is from the age of8-10 unproportionally much until the approximate age of 20, andsubsequently the axial length and thus the myopia are stable(intermediary myopia, glass strength of from approximately −4 to −8dioptries).

[0007] Finally, in rare cases a continuously growing axial lengththroughout the entire life can be seen, often connected with bulges inweak areas of the eye wall (scleraectasies). Here the myopia can reachextreme levels for glass strengths of up to approximately −40 dioptries(Excessive/pathological myopia).

[0008] The intermediary form,and the excessive one in particular, isconnected to a high risk of severe sight threatening complications suchas e.g. retinal detachment, degenerative changes in the yellow spot ofthe eye (macula degeneration) and glaucoma.

[0009] In the Western part of the world, severe myopia is among the mostimportant causes of blindness.

[0010] The group of myopic persons with a glass strength of more than−6, which comprises parts of the intermediary group and the entireexcessive group, comprises approximately 2% of the population, e.g. inDenmark approximately 100 000 persons (Curtin, B. J.: The myopys: Basicscience and clinical management, Harper and Row, Philadelphia, (1985)).

[0011] The cause of axial length conditional myopia is unknown.

[0012] It is however known that the longitudinal growth of the eye canbe increased by disturbance of the image formation on the retina, eg.experimentally by sewing together the eye lids of test animals (visualdeprivation) (Yinon, U., Current Eye Research, vol. 3, 4, 677-690,1984).

[0013] Administration of dopaminergic substances (apomorphine) in testanimals expose visual deprivation inhibits the development of myopia.(Iuvone, P. M., Invest. Ophthalmol. Vis. Sci., 32, 1674-77 (1991)).

[0014] U.S. Pat. No. 5,055,302, Laties and Stone, shows a method forcontrol of abnormal postnatal growth of the eye of an animal with theapplication of vasoactive intestinal peptide (VIP), PH1 or analogues ofsuch peptides. Such peptides were found to restrain the axiallongitudinal growth of a myopic eye.

[0015] U.S. Pat. No. 5,122,522, Laties and Stone, shows a method forcontrol of abnormal postnatal growth of the eye of an animal with theapplication of pirenzepine, an anticholinergic substance (M1 Muscarineantagonist). The axial longitudinal growth was inhibited byadministration of pirenzepine.

[0016] PCT-patent application publication No. WO 94/25034 Laties andStone, shows a method for control of abnormal postnatal growth of theeye of an animal with the application of tricyclical substances(antidepressiva). The axial longitudinal growth was inhibited byadministration of tricyclical substances.

[0017] However, in most cases myopia and hypermetropia are benignconditions which can easily be corrected by means of glasses. In orderto justify a medical treatment of these conditions, such treatment mustbe effective at relatively low dosages and roughly without any sideeffects, accordingly, as application of VIP, dopaminergic,anticholinergic or tricyclical substances is connected to risk of sideeffects as, simultaneously, the substances have considerablepsychochemical effects these prior art substances are not suitable forsuch treatment.

[0018] It is also a theory that the growth of the eye can be caused bypassive stretching of the scleral connective tissue (Norton, T. T.,Invest. Ophthalmol. Vis. Sci., 37(3), S324 (1996), Siegwart, Jr., J. T.,Invest. Ophthalmol. Vis. Sci., 37(3), S324 (1996)). Thus it is beenshown possible to trigger irreversible stretching of the sclera in youngrabbits by increasing the intraoccular pressure but it is not possibleto stretch the sclera in mature rabbits (Greene, P. R., ARVO Abstracts,1978, p. 297). However, tests with reduction of the intraoccularpressure by means of beta-blocking eye drops in humans developing myopiahave no effect (Jensen, H., Acta Ophthalmol., Suppl. 200, 69 (1991)).

[0019] There is no model for animal experiments which preciselycorresponds to the human conditions. As mentioned above, it is possibleto provoke myopia in some animals, e.g. cats and chicken, by sewingtogether the eye lids of newborn animals, but partly this experimentalmyopia develops much more rapidly than in humans, and partly thebiological age of the animal (newborn) does not correspond to the sameage when the myopia typically occurs in human (8-12 years). Furthermore,in chicken the sclera is considerably anomalous as it partly consists ofcartilage.

[0020] As the conditions of the eye related to the refractory system isextremely common and preventive treatment is to be applied to children,probably during years of treatment, effective substances should be verysafe. Accordingly, it would be a considerable improvement if a methodfor identification of a number of substances having an effect on thelongitudinal growth of the eye was available. Among substances suchidentified, it would subsequently be possible to select appropriatesubstances characterized by high efficiency and few side effects.

[0021] The present invention is related to methods for identification ofsubstances or groups of substances being candidates for the treatment orprevention of disease of the eye related to the longitudinal growth ofthe eye.

[0022] One of the methods for identification of effective substancesaccording to the present invention is related to the fact that,developementwise, the retinal pigment epithelium is a part of the retinaand forms an electrochemically active cell layer which is locatedbetween the choroid membrane of the eye and the neuronal part of theretina (neuroretina). It forms an electrically tight barrier and due toactive ion transport (based on the Na⁺-K⁺pump) it creates a differencein potential (the standing potential), the cornea-fundal potential,between the inner and the outer part of the eye of approximately 5 Mv.

[0023] Due to the anatomical conditions of the eye, this electricalfield is in the nature of a dipole with+at the cornea and−at the backpole of the eye. The size and changes of the standing potential can thusbe estimated with electrodes placed on each side of the eye by means ofsideway movements of the eye. (EOG examination (electroocculographywhich is well known in the art).

[0024] The standing potential is furthermore positively correlated withthe size of the so-called c-wave in ERG-recording. (electroretinography,which is well known in the art). According to one aspect of the presentinvention, the growth of the eye is related to the size and changes ofthe standing potential of the retinal pigment epithelium of the eye.

[0025] The transepithelial potential of the retinal pigment epitheliumis maintained by a difference in ionic concentration between thecytoplasm of the pigment epithelial cell and the internal and externalsurface. The state of the Ca²⁺-channels determines intracellular Ca²⁺.According to one aspect of the present invention, it is believed thatsubstances affecting the state of Ca²⁺ simultaneously affect thestanding potential created by the retinal pigment epithelium. The stateof the Ca²⁺-channels may be determined by [³H] ryanodine binding as theplant alkaloid ryanodine has been extensively used to study thefunctional interaction of the Ca²⁺-release channel (Meissner G:Ryanodine receptor/Ca²⁺ release channels and their regulation byendogenous effectors, Annu Rev Physiol 1994;56:485-508).

[0026] Accordingly, in a further aspect of the invention, the effect ofdifferent drugs on [³H]-ryanodine binding can be used to screen fordrugs that either strengthens the scleral connective tissue (increasesthe content of proteoglycans in sclera), or weakens it (decreases thecontent of proteoglycanes in sclera).

[0027] According to a still further theory behind the present invention,the biomechanical strength of the tissue is believed to be decisive forthe stretching of the sclera rather than a change of the intraoccularpressure as described in the prior art above. Substances increasing ordecreasing the strength of the scleral tissue may be used according tothe present invention for the treatment or prevention of diseaserelating to the longitudinal growth of the eye. In a further aspect,substances having a substantially selective effect on the posterior partof the sclera is preferred.

[0028] In a still further aspect of the present invention, substanceshaving an effect on the content of proteoglycanes in the scleral tissuemay be used for the treatment or prevention of disease relating to thelongitudinal growth of the eye.

[0029] Connective tissue such as eg. sclera mainly consists of scatteredcells in a base substance of proteoglycanes (proteins added toglycosaminoglycanes (branched polysaccharides)) and collagen fibres. Thebiomechanical properties of the tissue are determined by the content ofthese components and their organisation (Scott, J. E., Dermatan SulphateProteoglycans, Portland Press, 1993).

[0030] Furthermore, it has been demonstrated that fibroblasts in cellcultures may react to physiological electrical fields by taking on anoblong shape and orienting itself with the longitudinal axisorthogonally with the direction of the field (Erickson, C. A, et al.,Cell Biol, Vol. 98, January 1984, 296-307). It has also beendemonstrated that the connective tissue substance which is produced byfibroblasts may be determined by the shape of the cell (Evangilisti, R.et al, Eur. J. Histochem., 37, 161-172, 1993).

BRIEF DESCRIPTION OF THE PRESENT INVENTION

[0031] The present invention relates to a method for identification ofsubstances which have an effect, either inhibiting or increasing, on thelongitudinal growth of the human eye.

[0032] In another aspect, the invention relates to a method for treatingand/or preventing myopia and hypermetropia and to pharmaceuticalcompositions for such treatment, as well as for use of substances forthe preparation of medicaments useful for such treatment or prevention.

[0033] According to the present invention it is presumed that some thesesubstances act mainly on the retinal pigment epithelium and in additionon the receptors of the neuroretina.

[0034] In accordance with the present invention it is however believed,that the substances in tha last end excerts the treating or preventingeffect through an effect on the ion transport in and out of the cell inthe retinal pigment epithelium and thereby exerts its effect on thelongitudinal growth of the eye.

[0035] In one aspect the invention comprises screening of an optionalnumber of substances for the effect on the metabolical activity in theretinal pigment epithelium of the eye.

[0036] This effect may be measured by different methods. One of thesemethods relates to the activation of the Ca²⁺-release channel. ThisCa²⁺-release channel may be influenced by different effectors onreceptors on the cell membrane. Examples of such receptors are theryanodine receptor (RyR) and the inositol triphosphate (IP₃) receptor.

[0037] In another aspect, the present invention relates to thesurprising finding that substances affecting the size of the standingpotential are useful for the treatment or prevention of abnormal growthof the axial length of the eye.

[0038] Accordingly, by measuring of effect of the substances on theelectrochemical potential over the retinal pigment epithelium, theso-called “standing potential”, or the effect on the so-called “c-wave”by electro retinography (ERG), suitable substances for treating orpreventing conditions related to the longitudinal growth of the eye areeasily identified.

[0039] Substances increasing the standing potential or c-wave willinhibit the longitudinal growth of the eye and will thus be applicablefor treatment of myopia. Substances reducing the standing potential orc-wave will increase the longitudinal growth of the eye and will thus beapplicable for treatment of hypermetropia.

[0040] In a further aspect of the invention it is believed thatphysiological electrical fields are important in relation to theextracellular matrix of the scleral tissue and thereby to thebiomechanical properties of sclera. An increase of the electrical fieldis believed to influence the connective tissue cells in the sclera totake on an oblong form and deposit orthogonally on the field, i.e. inthe longitudinal direction of the sclera, making the tissue organisemore appropriately as concerns content of base substance and packing ofcollagen fibres. After long time treatment the sclera will be moreresistant to draft and thus less likely to give in to the intraoccularpressure, thus avoiding development of myopia.

[0041] In a further aspect of the invention, substances affecting thecomposition of the proteoglycanes may be used for the treatment ofabnormalities of the longitudinal growth of the eye.

[0042] In a further aspect, the invention comprises a method involvinganalysis of sclera tests from test animals after treatment (0-6 months)with substances influencing the sclera. Accordingly, the methodcomprises identifying one or more of the following elements: the effectof the substance on the proteoglycanes; the distribution between variousglycosaminoglycane types; and the content of collagen specific aminoacids. The analysis may additionally comprise identifying the density ofcollagen fibrils and the distribution between various fibrils diametersby means of electron microscopy.

[0043] According to the present invention, it is possible that theeffect on the composition of the proteoglycanes and/or the collagenspecific amino acid present in the connective tissue of the sclera ofthe eye is due to an influence on the metabolical activity in theretinal pigment epithelium of the substance of the eye.

[0044] Substances increasing the content of proteoglycanes and collagenspecific amino acids will strengthen the connective tissue in thesclera, reduce the longitudinal growth of the eye and thus work againstmyopia. Substances increasing the content of dermatane sulphate inproportion to the other glycosaminoglycanes will furthermore strengthenthe connective tissue in the sclera and work-against myopia. Substancesincreasing the density of collagen fibrils and increasing the diameterof the fibrils will furthermore strengthen the connective tissue in thesclera and work against myopia.

[0045] Substances reducing the content of proteoglycanes and collagenspecific amino acids will weaken the connective tissue in the sclera,increase the longitudinal growth of the eye and thus work againsthypermetropia. Substances reducing the content of dermatane sulphate inproportion to the other glycosaminoglycanes will weaken the connectivetissue in the sclera and work against hypermetropia. Substances reducingthe density of collagen fibrils and reducing the diameter of the fibrilswill furthermore weaken the connective tissue in the sclera and workagainst hypermetropia.

[0046] In a further aspect, the invention relates to a method foridentifying substances affecting the composition of the proteoglycanesof the sclera of the eye, and thereby exert an effect of the strength ofthe connective tissue.

BRIEF DESCRIPTION OF THE FIGURES

[0047]FIG. 1 shows the inhibiting effect of a combination of caffeineand L-cystine on the longitudinal growth of the human eye.

[0048]FIG. 2 shows an example of an analysis curve for amino acids bythe application of HPLC.

[0049]FIG. 3 shows the general formula of xanthine and of threederivatives thereof, caffeine, theophylline and theobromine,respectively. As appears from the figure, caffeine and theobromine aresubstituted in position 7 by a methyl group.

[0050]FIG. 4 shows the content of hydroxyproline in anterior andposterior sclera after treatment with the substances described inExample 2.

[0051]FIG. 5 shows the content of hydroxylysine in anterior andposterior sclera after treatment with the substances described inExample 2.

[0052]FIG. 6 shows the content of proline in anterior and posteriorsclera after treatment with the substances described in Example 2.

[0053]FIG. 7 shows the content of proteoglycanes in anterior andposterior sclera after treatment with the substances described inExample 2.

[0054]FIG. 8 shows the content of hydroxyproline in anterior andposterior sclera after treatment with the substances described inExample 4.

[0055]FIG. 9 shows the content of hydroxylysine in anterior andposterior sclera after treatment with the substances described inExample 4.

[0056]FIG. 10 shows the content of proline in anterior and posteriorsclera after treatment with the substances described in Example 4.

[0057]FIG. 11 shows the content of proteoglycanes in anterior andposterior sclera after treatment with the substances described inExample 4.

[0058]FIG. 12 shows the correlation between the effect of differentmethylxanthines on the content of proteoglycanes in posterior sclera andthe effect of the same methylxanthines on[³H] ryanodine binding capacitycompared to that of the control, xanthine. The values appears from Table13. Caffeine is represented by 1,7-dimethylxanthine since this is themost dominating metabolite in serum of rabbits after feeding withcaffeine. As appears from the figure, a ³H ryanodine binding exceeding130% compared to xanthine seems to be needed to produce a positiveeffect on the content of proteoglycanes in sclera.

[0059] Interesting embodiments of the aspects of the invention appearfrom the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0060] The present invention applies the surprising finding thatsubstances which have an increasing effect on the standing potential orc-wave of the eye by ERG will increase the scleral connective tissuesability to resist abnormal growth or stretching, and thus work againstdevelopment of myopia. The increased resistant may according to thepresent invention be due to increase in the content of proteoglycanesand/or collagen specific amino acids such as hydroxyproline,hydroxylysine and proline. Furthermore, an increase in the diameter ofthe collagen fibrils may also contribute to the effect according to theinvention.

[0061] It is furthermore believed that the specific glycosaminoglycanesof the proteoglycanes may have an effect on the structure so that anincreased proportion of e.g the content of dermatane sulphate inpercentages is related to increased mechanical strength of the scleraand thus also work against development of myopia. Similarly, a decreaseworks against development of hypermetropia

[0062] In a further embodiment, the invention applies the surprisingfinding that substances which reduce the standing potential or c-wave ofthe eye by ERG will, in similarity, reduce the content of proteoglycanesand/or collagen specific amino acids, reduce the content of dermatanesulphate in percentages, reduce the diameter of the collagen fibrils,and thus reduce the scleral connective tissues ability to resiststretching, and thus reduce the level of hypermetropia.

[0063] In order to examine whether a substance is able to produce achange in the connective tissue substance of the sclera, it is normallynecessary to treat test animals for a long time, presumably severalmonths. Therefore it would be very resource consuming to test a largenumber of substances by means of this method alone. By confining oneselfto testing substances which influence the standing potential or c-waveof the eye by ERG, it becomes much more likely to identify substanceswhich with few or no side effects are able to influence the scleralconnective tissue and thus be applicable for treatment of myopia orhypermetropia.

[0064] As will be described in the following, the invention furtherrelates to the surprising finding, that substances effecting themetabolic state of the cells of the retinal pigment epithelium are alsoable to induce the effects described above. This effect may by detectedin different ways, such as by the state of the Ca²⁺-channels. Inaddition, the state of the Ca²⁺-channels may be determined by ³Hryanodine binding, or in another preferred embodiment of the presentinvention, by the inositol triphosphate (IP₃) receptor. Inositoltriphosphate increase intracellular calcium.

[0065] Accordingly, substances binding to the receptors and therebyresults in an increase in the intracellular calcium ions may be utilizedfor the treatment of myopia, and substances which inhibit the receptorsmay be used in the treatment of hypermetropia in accordance with theteaching of the present invention.

[0066] The method according to the invention for screening substanceseffective of treating disorders of the eye related to the axial lengthof the eye comprises identifying substances having an effect on theretinal pigment epithelium. It is believed that substances having aneffect on the more primitive pigment epithelium and a rather limitedeffect on neural tissue will result in a treatment having less sideeffects compared to the use of substances having a substantial effect onthe central nervous system.

[0067] Accordingly, the present invention in a still other aspectrelates to the use of substances wherein the effect on the pigmentepithelium is primarily on the ion exchange over the cell membrane. Thiseffect may be regarded as a metabolic effect. Accordingly, in a furtheraspect of the invention, the method is for screening substanceseffective of treating disorders of the eye related to the axial lengthof the eye and comprises identifying substances having an effectsubstantially on the pigment epithelium compared to the effect on theneuroretina.

[0068] The present invention relates in its broad definition to a methodfor screening substances effective of treating disorders of the eyerelated to the axial length of the eye. The method essentially comprisesthe identification of substances having an effect on the retinal pigmentepithelium of the eye as this effect on the retinal pigment epitheliumhas a clear connection to the function of the control of the axialgrowth of the eye.

[0069] As the function of the retinal pigment epithelium is possiblyalso affected by a direct or receptor effect on neuroretina, the effecton the retinal pigment epithelium may be through an effect of thesubstance on the neuroretina. In a further aspect of the invention, thesubstance may have an effect directly on the neuroretina together with adirect effect on the retinal pigment epithelium. In a further aspect theeffect on the neuroretina also induces an effect on the retinal pigmentepithelium.

[0070] The ion exchange pumping on the cell membrane is driven by cAMP.An effect of a substance to be screened may exert an inhibiting orincreasing effect on the pump and thereby on the function of theretinal-epithelium. In other words it could be expressed by the factthat the substances to be screened are selected by the metabolic effectof the substance on the pigment epithelium.

[0071] One preferred method according to the invention is to identifythe effect on the pigment epithelium by means of the standing potentialand/or on the c-wave by electro retinography (ERG). In a further aspect,also the effect on the a-wave and/or on the b-wave in the neuroretina ismeasured whereby it is possible to identify substances having an effectsubstantially on the retinal pigment epithelium compared to an effect onthe neuroretina where the latter is shown as an effect on the a-waveand/or on the b-wave.

[0072] In order to identify substances effective of inhibiting thelongitudinal growth of the eye, substances increasing the standingpotential and/or the c-wave are selected. These substances may be usedfor the treatment or prevention of myopia.

[0073] In order to identify substances effective of increasing thelongitudinal growth of the eye, substances decreasing the standingpotential and/or the c-wave are identified. These substances may be usedfor the treatment or prevention of hypermetropia.

[0074] In a further embodiment of the invention a method for screeningsubstances effective of treating disorders of the eye related to theaxial length of the is eye disclosed. The method comprises identifyingsubstances having an effect on the composition of the proteoglycanesand/or the collagen specific amino acid present in the connective tissueof the sclera of the eye.

[0075] This method may in one embodiment be by treating an animal withthe substance and measuring the effect on the composition of theconnective tissue of the sclera.

[0076] In another embodiment the method comprises adding the substanceto a tissue culture comprising retinal pigment epithelium andfibroblasts and identify the impact of the substance on the productionand composition of the proteoglycanes and/or the collagen specific aminoacid produced by the fibroblasts in the tissue culture.

[0077] The method according to the invention also comprises identifyingsubstances effective of inhibiting the longitudinal growth of the eye.These substances are such substances which increase the content ofproteglycanes of the sclera, and may be used for the treatment orprevention myopia.

[0078] Accordingly, substances effective of increasing the longitudinalgrowth of the eye are the substances decreasing the content ofproteoglycanes of the sclera. These substances may be used for thetreatment or prevention of hypermetropia.

[0079] The effect of the substance on the proteoglycanes can generallybe identified within a period from as early as 1 day to about 12 weeksfrom the start of the treatment. However, normally at least one week oftreatment is necessary for having an effect which can be measured withthe existing analytical methods.

[0080] To apply an animal model to a human effect, it is generallypreferred that the test animal is a mammal. However other animals suchas birds and reptiles may employed in the present method.

[0081] As is evident for the above explanation, and due to thesurprising finding that an effect on the retinal pigment epithelium maybe utilized for treatment of disorders of the axial length of the eye,any substance may be subjected to the method according to the invention.

[0082] In one embodiment the invention relates to the screening of asubstance selected from the group consisting of prostaglandine andanalogues thereof; and compounds of the general formula I, II or III

[0083] wherein R¹, R³, R⁷, and R⁹ are independently selected from thegroup consisting of hydrogen, optionally substituted C₁₋₂₀-alkyl,optionally substituted C₂₋₂₀-alkenyl, optionally substitutedC₄₋₂₀-alkadienyl, optionally substituted C₆₋₂₀-alkatrienyl, optionallysubstituted C₂₋₂₀-alkynyl, optionally substituted C₁₋₂₀-alkoxycarbonyl,optionally substituted C₁₋₂₀-alkylcarbonyl, formyl, optionallysubstituted aryl, optionally substituted aryloxycarbonyl, optionallysubstituted arylcarbonyl, optionally substituted heteroaryl, optionallysubstituted heteroaryloxycarbonyl, optionally substitutedheteroarylcarbonyl, carbamoyl, mono- and di(C₁₋₂₀-alkyl)aminocarbonyl,mono- and di(C₁₋₂₀-alkyl) amino-C₁₋₂₀-alkyl-aminocarbonyl, and halogensuch as fluoro, chloro, bromo-or iodo, and

[0084] R⁸ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₂₀-alkyl, optionally substituted C₂₋₂₀-alkenyl,optionally substituted C₄₋₂₀-alkadienyl, optionally substitutedC₆₋₂₀-alkatrienyl, optionally substituted C₂₋₂₀-alkynyl, optionallysubstituted C₁₋₂₀-alkoxy, optionally substituted C₂₋₂₀-alkenyloxy,carboxy, hydroxy, optionally substituted C₁₋₂₀-alkoxycarbonyl,optionally substituted C₁₋₂₀-alkylcarbonyl, formyl, optionallysubstituted aryl, optionally substituted aryloxycarbonyl, optionallysubstituted aryloxy, optionally substituted arylcarbonyl, optionallysubstituted arylcarbonyl, optionally substituted heteroaryl, optionallysubstituted heteroaryloxycarbonyl, optionally substituted heteroaryloxy,optionally substituted heteroarylcarbonyl, amino, mono- anddi(C₁₋₂₀-alkyl)amino, carbamoyl, mono- and di(C₁₋₂₀-alkyl)aminocarbonyl,amino-C₁₋₂₀-alkylaminocarbonyl, mono- and di(C₁₋₂₀-alkyl)aminocarbonyl,amino-C₁₋₂₀-alkylaminocarbonyl, optionally substitutedC₁₋₂₀-alkylcarbonylamino, guanidino, carbamido, optionally substitutedC₁₋₂₀-alkanoyloxy, sulphono, optionally substitutedC₁₋₂₀-alkylsulphonyloxy, nitro, sulphanyl, optionally substitutedC₁₋₂₀-alkylthio, and halogen such as fluoro, chloro, bromo or iodo.

[0085] Preferably, R¹, R³, R⁷, and R⁹ are independently selected fromthe group consisting of hydrogen, optionally substituted C₁₋₆-alkyl,optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,optionally substituted aryl, optionally substituted arylcarbonyl,optionally substituted heteroaryl, and optionally substitutedheteroarylcarbonyl, and

[0086] R⁸ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionallysubstituted C₂₋₆-alkynyl, optionally substituted C₁₋₆-alkoxy, optionallysubstituted C₂₋₆-alkenyloxy, carboxy, hydroxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,optionally substituted aryl, optionally substituted aryloxycarbonyl,optionally substituted aryloxy, optionally substituted arylcarbonyl,optionally substituted arylcarbonyl, optionally substituted heteroaryl,optionally substituted. heterarloxycarbonyl, optionally substitutedheteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, optionally substitutedC₁₋₆-alkylcarbonylamino, guanidino, carbamido, optionally substitutedC₁₋₆-alkanoyloxy, sulphono, optionally substitutedC₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, optionally substitutedC₁₋₆-alkylthio, and halogen such as fluoro, chloro, bromo or iodo.

[0087] In a further embodiment, R¹, R³, R⁷ and R⁹ are independentlyselect from the group consisting of hydrogen, optionally substitutedC₁₋₆₋alkyl, optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted aryl, and

[0088] R⁸ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionallysubstituted C₂₋₆-alkynyl, optionally substituted C₁₋₆-alkoxy, optionallysubstituted C₂₋₆-alkenyloxy, carboxy, hydroxy, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylcarbonyl, amino, nitro, sulphanyl, and halogen such as fluoro,chloro, bromo or iodo.

[0089] In a further embodiment the invention relates to the screening ofa substance selected from the following group of substances selectedbased on different criteria with respect to inhibiting or stimulatingeffects known from the litterature. The group comprises prostaglandineand analogues thereof such as F2 alpha analogues including PhXA41,prostaglandin receptor agonists including PGF 2 alpha, 17-phenyl trinorPGE2, and U46619; adenosine A2-receptor agonists such as 5′(N-ethyl)-carboxamido adenosine, alpha-2D adrenergic receptor agonistsand antagonists; alpha-2-adrenergic agonist such as UK-14,304;prostaglandin agonists such as 16-phenoxy-PGF2 alpha, cloprostenol,17-phenyl-PGF2 alpha, fluprostenol, and PhXA85; insulin; bumetanide,petides such as bradykinin, arginine vasopressin, bombesine, substanceP, pituitary adenylate cyclase activating polypeptide, atrialnatriuretic peptide, somatostatin analogues such asTyr11-somatostatin-14, Leu8, D-Trp22, and Tyr25-somatostatin-28;muscarine receptor agonists and antagonists such as the Carbachol(stimulates production of inositolphosphate by way of M3 muscarinicreceptors), 4-diphenylacetoxy-N-methylpiperadine methiodide, atropin andpirencepine (blocking the effect); calcitriol recepter agonist andantagonists, acetylcholin (increases introcellular calcium by inositoltriphosphate receptors), nonsteroidal antiinflammatory drugs such asniflumic acid; Thapsigargin; A23187; phosphodiesterase inhibitors suchas rolipram and zaprinast, 4-chloro-3-ethyl-phenol; Bastidin;Veratridine; estrogens and derivatives thereof; Tamoxifen; and Bay K8644(1,4-Dihydro-2,6-dimethyl-5-nitor-4-(2(triflouromethyl)-phenyl)-3-pyridinencarboxylicacid methyl ester.

[0090] Upon screening, substances selected due their ability of treatingmyopia or hypermetropia based on the criteria defined in the presenttext may be used for the preparation of a medicament for treating orpreventing disorders of the eye related to the axial length of the eyefor a method for treating or preventing the disorder by administrationof a pharmaceutically effective amount of the substance to an individualin need thereof.

[0091] In a further embodiment, the present invention relates to amethod for treating and/or preventing myopia of a human eye comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of one or more substances selected from caffeine;1,7-dimethylxanthine (paraxanthine), 7-methylxanthine (heteroxanthine),isobutylmethylxanthine (IBMX) and derivatives; 3-methylxanthine,1-methylxanthine, 1-Hexyl-3,7-dimethylxanthine (pentifylline);1,7-Dimethyl-xanthine; 1,3-Dipropyl-7-methyl-xanthine; 7-Propylxanthine;7β-Chloroethyl -1,3-dimethylxanthine; 3,7-Dimethyl-1-propargyl-xanthine;3-Propylxanthine; 1-(5-Oxohexyl)-3,7-dimethylxanthine (pentoxyfylline);3-Isobutyl-1-methylxanthine; 3,9-Dimethylxanthine8-Cyclopentyl-1,3-dimethylxanthine;1,3-Bis(3-methylbut-2-butenyl-7-methylxanthine;3,7-Dihydro-7-methyl-1,3-dipropyl-1H-purine-2,6-dione;7-Methyl-1,3-diprenylxanthine(7-methyl-1,3-dipropyl-xanthine;7-Ethoxyznethyl-1-(5-hydroxy-5-methylhex-methylxanthine (Torbafylline,“HWA 448”); 1-(5 hydoxy-5-methylhexyl)-3-methyl-7-propylxanthine (A80.2715); 3,7-Dimethyl-1-(5-oxyhexyl)-xanthine (Pentoxifylline,“Trental”);3,7-Dimethyl-1-(5-hydroxyhexyl)-xanthine(Hydroxypentoxifylline); 1-Hexyl-3,7-dimethylxanthine (Pentifylline,“Cosaldon”); 3,7-Dimethyl-1-proparglyxanthine (DMPX);(E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837)(Lisofylline); 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine(Albifylline, “HWA 138”): 3-Methyl-1-(5′-oxohexyl)-7-propylxanthine(Propentofylline, “HWA 285”); 1-(5-Hydroxyhexyl)-3,7-dimethylxanthine(BL 194); (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KF17.837); 1,3-di-n-butyl-7-(2′oxopropyl)-xanthine (Denbufylline);1-n-butyl-3-n-propylxanthine (XT-044);7-(2,3-dihydroxypropyl)-theophylline (Dyphylline);7-Methyl-8-(2-hydroxy-N-methylethylamino)-theophylline (Cafaminol);7-(1,3-Dioxolan 2-ylmethyl)-theophylline (Doxofylline);7-(2-Hydroxyethyl)-1,3-dimethyixanthine (Etofylline);7-(2-Hydroxypropyl)-1,3-dimethylxanthine (Proxyphylline);Pyridoxine-O-(theophyllin-7-ylethyl)sulphate (Pyridofylline);7-(2-(3-diethylcarbamoylpropionyloxy)ethyl)-theophylline(Suxamidofylline); Piperazine bis(theophyllin-7-ylacetate)(Acepifylline);8-benzyl-7-(2-(N-ethyl-N-2-hy-droxyethylamino)ethyl)theophylline(Bamifylline); 2-amino-2-methylpropan-1-ol theophyllinate (Bufylline);7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine (Diprophylline);7-(2-diethylamoinoethyl) 1,3-dimethylxanthine camphor 10 sulphonate(Etamiphylline Camsylate); 3-Propylxanthine (Enprofylline);4-amino-8-chloro-1-phenyl-(1,2,4)-triazolo (4,3-a)quinoxaline (CP66713); cysteine/cystine; glycine, forskoline; alpha-2-adrenergicagonist such as brimonidine (UK-14,304), clonidine, apraclonidine,dapiprazole, moxonidine (4-chloro-N-(4,5dihydro-1H-imidasol-2yl)-6-methoxy-2-methyl-5-pyridinamine),medetomidine, oxymetazoline, or derivatives thereof; peptides such asbradykinin, arginine vasopressin including V2 agonists, bombesine,substance P, pituitary adenylate cyclase activating polypeptide;somatostatin analogues such as Tyr11-somatostatin-14, Leu8, D-Trp22, andTyr-somatostatin-28 including agonists of somatostatin sst2 receptors,neuropeptide Y including agonists of Y2 receptors, and anlogues of thesepeptides; calcitriol or analogues of calcitriol or Vitamin D; muscarinereceptor agonists such as the Carbachol, acetylincholine or analoguesthereof; nonsteroidal antiinflammatory drugs such as niflumic acid;prostaglandine and analogues thereof such as F2 alpha analoguesincluding PhXA41 (latanoprost), prostaglandin receptor agonistsincluding PGF 2 alpha, 17-phenyl trinor PGE2, and U46619 FP, EP1, and TPreceptor agonists), UF 021, 16-phenoxy-PGF2 alpha, cloprostenol,17-phenyl-PGF2 alpha, fluprostenol, and PhXA85; Thapsigargin, A23187,Phosphodiesterase inhibitors including rolipram and Zaprinast,4-chloro-3-ethylphenol and Bastidin, veratridine, esterogens includinganalogues thereof; Bay K 8644(1,4-Dihydro-2,6-dimethyl-5-nitor-4-(2(triflouromethyl)-phenyl)-3-pyridinencarboxylicacid methyl ester; angiotensin converting enzyme inhibitors, inparticular captopril (SQ 14225); adenosine A2-receptor agonists such as5′ (N-ethyl)-carboxamido adenosine and 8-phenylaminoadenosine (CV-1808);Candoxatril (neutral endopeptidase 24.11 (NEP) inhibitor);Met-enkephalin, alphaendorphin or derivatives; and mixtures thereof.

[0092] L-cystine is a sulphurous amino acid which is a component ofproteins, e.g. collagen, where the above sulphurous cross-links derivefrom it. The L-cystine is thus contained in ordinary food.

[0093] In a preferred embodiment, the method comprises use of a mixtureof two or more substances having an additive effect on the myopia. In apreferred embodiment, the mixture has a synergistic effect. Both theadditive effect and the synergistic effect may by measured by means ofthe methods described herein, such as by ERG.

[0094] In a still further embodiment, the present invention relates tomethods for treating and/or preventing hypermetropia of a human eyecomprising treatment by means of therapeutically effective amounts ofone or more substances selected from theophylline, xanthine,1,9-dimethylxanthine; 1,3-Dipropyl-8-(2-(5,6-epoxynorbonyl)-xanthine;8-Cyclopentyl-1,3-dipropylxanthine (CPDPX); 8-Sulphophenyltheophylline;1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433);(1-Propyl-11C)8-dicyclo-propylmethyl-1,3-dipropylxanthine (11C)KF15372and 11C-ethyl and 11C-methyl derivatives thereof; 8-Benzyl-7,(2-(ethyl(2-hydroxyethyl)amino)ethyl)theophylline (Bamiphylline);8-Cyclopentyl-3-(3-((4-(flourosulfonyl)benzoyl)oxyl)prd-pyl)-1-propylxanthine;1,3-Dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyl-oxyphenyl)xanthine;8-(3-chlorostyryl)caffeine; 8-cyclopentyltheophylline; 8-(noradamantan-3yl)-1,3-dipropylxanthine (KW-3902);1,3-Dipropyl-8-(3-noradamantyl)-xanthine;1,3-Dipropyl-8-(4-sulphophenyl)-xanthine;1,3-Dipropyl-8-(2-amino-4-chlorophenyl)-xanthine;7β-Hydroxyethyl-1,3-dimethylxanthine;7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine;8-Chloro-1,3-dimethyixanthine; 1,3,9-Trimethylxanthine; 8-Propionicacid-1,3-dimethylxanthine; 7,9-Dimethylxanthine;8-Phenyl-1,3-dimethylxanthine; 7-Acetic acid-1,3-dimethylxanthine;9-Propylxanthine; 9-Methylxanthine; 8-Methylxanthine;8-(p-Sulfophenyl)-1,3-dimethylxanthine; 1,9-Dimethylxanthine;hypoxanthine; fluoxetine; L-ornithine; azetazolamide; bumetanide;Tamoxifen and other estrogen antagonists, the calmodulin antagonist J8,calcium antagonists including nimodipine and nicardipine, Endothelinagonist, in particular sarafotoxin S6c (selective ETB receptor agonist);Dorzolamide (MK-507), sezolamide and MK-927(thienothiopyran-2-sulfonamide-derivatives carbonic anhydraaeinhibitors), methazolamide, ethoxzolamide, leuenkephalin or dervatives;and mixtures thereof.

[0095] In a preferred embodiment, the method comprises use of a mixtureof two or more substances having an additive effect on thehypermetropia. In a still more preferred embodiment, the mixture has asynergistic effect. Both the additive effect and the synergistic effectmay by measured by means of the methods described herein, such as byERG.

[0096] Use of a mixture may also be preferred when minor total dosagesof each of the substances are preferred compared to a higher totaldosage of only one substance.

[0097] The active substance or mixture of substances according to theinvention may be administered orally, parenterally, transdermally ortransmucosally e.g. as an intranasal formulation or as eyedrops. Inaddition, a local application in the eye may result in a substantiallocal concentration of the substance in the retinal area due to theanatomical circumstances of the eye whereby a less systemic effect isachieved. This is e.g. the fact where the substance is applied topicallyto the eye and where the drainage of the substance is by the uveoscleralpathway.

[0098] The pharmaceutical composition according to the inventioncomprising the active substance or mixture of substances may beadministered in the form of a pharmaceutical composition which is atablet, a capsule, a sustained release capsule comprising micro capsulesof the active ingredient, a solution or suspension, a device fortransdermal application, or a suppository or implant, or in any otherconventional formulation.

[0099] As the treatment or prevention of abnormal growth of the eye is alongterm treatment to children, the active substance or mixture ofsubstances may be incorporated into a general daily vitamin tablet or beincorporated into foodstuff, so-called functional foods, includingsoftdrinks, milk, bread, etc.

[0100] It is also an aspect of the present invention, that theindividual substances may be interchanged during a treatment period, orthat one substance is administered in an individual dosage, e.g in themorning, and another substance is administered in the evening.

[0101] In a further aspect of the invention the active ingredient isderived from the biological natural sources. Several methylxanthinesnaturally occurs in plants. More than 60 plant species throughout theworld have been identified as containing 1,3,7-trimethylxanthine,1,7-dimethylxanthine, 1,3-dimethylxanthine, 1-methylxanthine,3-methylxanthine, or 7-methylxanthine. These plants includes the speciescoffea, camellia, cola, paullinia (guarana), iles (maté), theobroma,citrus, geraniaceae, copermecia, phaseolul, mungo, soya bean, betavulgaris, sugar cane, and xanthophycae. Since the active substancesoften represents different steps in the synthesis or degradation of morecomplex methylxanthines, several xanthines may be present in the sameplant in concentrations that variate with the season of the year.

[0102] Harvesting the plant at different periods of the season, andusing different extraction methods will result in extracts containinghigh concentration of certain methylxanthines with only minorcontributions of other, and less desired methylxanthines. In a furtherembodiment of the invention, a extraction method is described thatresults in a composition rich in 7-methylxanthine, taking advantage ofthe fact that 7-methylxanthines is more easily dissolved than the othermethylxanthines.

[0103] Other embodiments relates to extraction of beta vulgaris, sugarcanes, xanthophycae and other plants comprising 7-methylxanthines.

[0104] Depending on the exact dissolving properties of the desiredactive ingredient, the extraction method may be adapted for the specificplant as well as for the desired active ingredient.

[0105] Examples of a suitable extraction method is given below inExamples 6 and 7.

[0106] In a still other aspect, the active ingredient for treating orpreventing disease of the longitudinal growth of the eye may be producedby genetic engineering such as by transgenic plants expressing theactive ingredient or by other biotechnological methods.

[0107] In addition to genetic manipulation, the plant material, for thepurpose of increasing the yield of certain methylxanthines from theplant material, the plant may be subjected to treatment with substancesthat block or facilitate certain enzymes that determines the metabolismof the metylxanthines. As an example of this, treatment of coffee plantswith allopurinol will result in accumulation of great amounts of7-methylxanthine in the plant (Ashihara H (1996). Catabolism of caffeineand related purine alkaloids i leaves of coffea arabica; L. Planta1998:334-339)

[0108] Registration of c-Wave at ERG in animals (e.g. rabbits) is awell-developed examination technique (Skoog, K. O., Nilsson, S. E. G.,Acta Ophthalmol. (Kph), 52: 759-773 (1974), Jarkman, S., Skoog, K. O.,Doc. Ophthalmol., 60: 383-392 (1985)). Also intraoccular administrationof test substances for test animals is also a well-described technique(Textorius, O., Doc. Ophthalmol., 63:349-358 (1986)). Alternatively,test substances can be administered intravenously (Jarkman, S., Doc.Ophthalmol. 60: 375-382 (1985)).

[0109] In addition, it is possible to determine the effect of testsubstances on the standing potential and c-wave at ERG indirectly bymeans of an in-vitro arrangement with a retinal pigmentepithelium-choroidea preparation, and to determine the transepithelialpotential (Kawasaki, K., Doc. Ophthalmol., 63: 375-381 (1986))

[0110] By means of such examination techniques which can facilitatequick examinations it is according to the present invention possible toexamine a large number of substances in various concentrations and todetermine which substances have a strong effect on the activity of thepigment epithelium of the retina.

[0111] Determination of the content of proteoglycanes in tissue samplescan be performed by means of several well-developed methods (eg.Björnsson, S., Analytical Biochemistry 210, 282-291 (1993)).

[0112] The content of the collagen specific amino acids (hydroxyproline,hydroxylysine, and proline) can be determined eg. by means ofautoanalysis (Blumenkrantz, N., Clin. Biochem. 13: 177-183 (1980)) or bymeans of high pressure liquid chromatography (HPLC) or other methods. Amethod for determination of the content of collagen specific amino acidsin connective tissue by means of application of HPLC has been describedin detail below.

[0113] A method for determination of the content of dermatane sulphatein percentages in relation to the other glycosaminoglycanes (celluloseacetate electroforese) has been described in detail below.

[0114] The following Table 1 shows a-number of specific preferredxanthine substances according to the present invention effective fortreating and/or preventing myopia, and in Table 2 for hypermetropia.TABLE 1 Substances effective for treating and/or preventing myopia 1.1,3-Bis(3-methylbut-2-butenyl-7-methylxanthine 2.3,7-Dihydro-7-methyl-1,3-dipropyl-1H-purine-2,6-dione 3.7-Methyl-1,3-diprenylxanthine(7-methyl-1,3-dipropyl- xanthine¹ 4.7-Ethoxymethyl-1-(5-hydroxy-5-methylhexyl)3- methylxanthine(Torbafylline, “HWA 448”) 5. 1-(5hydoxy-5-methylhexyl)-3-methyl-7-propylxanthine (A 80.2715) 6.3,7-Dimethyl-1-(5-oxyhexyl)-xanthine (Pentoxifylline, “Trental”) 7.3,7-Dimethyl-1-(5-hydroxyhexyl)-xanthine (Hydroxypentoxifylline) 8.1-Hexyl-3,7-dimethylxanthine (Pentifylline, “Cosaldon”) 9.3,7-Dimethyl-1-proparglyxanthine (DMPX)²) 10.(E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF 17837)(Lisofylline) 11. 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine(Albifylline, “HWA 138”) 12. 3-Methyl-1-(5′-oxohexyl)-7-propylxanthine(Propentofylline, “HWA 285”) 13. 1-(5-Hydroxyhexyl)-3,7-dimethylxanthine(BL 194) 14. (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine(KF 17.837)¹⁾ 15. 1,3-di-n-butyl-7-(2′oxopropyl)-xanthine (Denbufylline)16. 1-n-butyl-3-n-propylxanthine (XT-044) 17.7-(2,3-dihydroxypropyl)-theophylline (Dyphylline) 18.7-Methyl-8-(2-hydroxy-N-methylethylamino)-theophylline (Cafaminol) 19.7-(1,3-Dioxolan 2-ylmethyl)-theophylline (Doxofylline) 20.7-(2-Hydroxyethyl)-1,3-dimethylxanithine (Etofylline) 21.7-(2-Hydroxypropyl)-1,3-dimethylxanthine (Proxyphylline) 22.Pyridoxine-O-(theophyllin-7-ylethyl)sulphate (Pyridofylline) 23.7-(2-(3-diethylcarbamoylpropionyloxy)ethyl)theophylline(Suxamidofylline) 24. Piperazine bis(theophyllin-7-ylacetate)(Acepifylline) 25.8-benzyl-7-(2-(N-ethyl-N-2-hydroxyethylamino)ethyl)theo- phylline(Bamifylline) 26. 2-amino-2-methylpropan-1-ol theophyllinate (Bufylline)27. 7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine Diprophylline) 28.7-(2-diethylamoinoethyl)-1,3-dimethylxanthine camphor 10 sulphonate(Etamiphylline Camsylate) 29. 3-Propylxanthine (Enprofylline) 30.4-amino-8-chloro-1-phenyl-(1,2,4)-triazolo(4,3- a)quinoxaline (CP71366)¹⁾

[0115] TABLE 2 Substances effective for treating and preventing ofhypermetropia 31. 1,3-Dipropyl-8-(2-(5,6-epoxynorbonyl)-xanthine³⁾ 32.8-Cyclopentyl-1,3-dipropylxanthine (CPDPX)⁴⁾ 33.8-Sulphophenyltheophylline 34. 1,3-Dipropyl-8-(4-acrylate)phenylxanthine(BW-A1433)⁵⁾ 35. (1-Propyl-11C)8-dicyclopropylmethyl-1,3-dipropylxanthine (11C) KF15372 and 11C-ethyland 11C-methyl derivatives thereof All⁴⁾ 36.8-Benzyl-7,(2-(ethyl(2-hydroxyethyl)amino)ethyl)theo- phylline(Bamiphylline) 37.8-Cyclopentyl-3-(3-((4-(flourosulfonyl)benzyl)oxyl)Pro-pyl)-1-propylxanthine³⁾ 38.1,3-Dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyl-oxyphenyl)xanthine 39. 8-(3-chlorostyryl)caffeine 40.8-cyclopentyltheophylline³⁾ 41. 8-(noradamantan-3yl)-1,3-dipropylxanthine (KW-3902) 42.1,3-Dipropyl-8-(3-noradamantyl)-xanthine³⁾ 43.1,3-Dipropyl-8-(4-sulphophenyl)-xanthine 44.1,3-Dipropyl-8-(2-amino-4-chlorophenyl)-xanthine 45. Hypoxanthine

[0116] TABLE 3 Effect of xanthines on [³H] ryanodine binding to skeletalRyR Bound [³H] ryanodine, % of control +3 mmol/l +1 mmol/l AMP AMPPCPControl (-xanthine) 100 100 100 1-Hexyl-3,7-dimethylxanthine 549 ± 33*449 ± 28* 414 ± 47* (pentifylline) 1,7-Dimethyl- 240 ± 27* 378 ± 34* 360± 28* xanthine 1,3-Dipropyl-7-methyl- 220 ± 23* 326 ± 30* 295 ± 23*xanthine 7-Propylxanthine 216 ± 25* 234 ± 14* 270 ± 12*7β-Chloroethyl-1,3-dimethyl- 220 ± 27* 256 ± 34* 230 ± 9* xanthine3,7-Dimethyl-1-propargyl- 193 ± 15* 201 ± 33* 230 ± 6* xanthine3-Propylxanthine 211 ± 13* 203 ± 14* 226 ± 14* 7-Methylxanthine 204 ±25* 214 ± 15* 225 ± 11* 1-(5-Oxohexyl)-3,7-dimethyl- 187 ± 16* 185 ± 25*188 ± 5* xanthine (pentoxyfylline) 1,3,7-Trimethylxanthine 155 ± 22* 164± 11* 182 ± 18* (caffeine) 1-Methylxanthine 153 ± 15* 167 ± 16* 179 ±22* 3-Isobutyl-1-methyl- 137 ± 16* 139 ± 11* 175 ± 20* xanthine1,3-Dimethylxanthine 136 ± 29* 148 ± 8* 170 ± 25* (theophylline)3,7-Dimethylxanthine 124 ± 22* 136 ± 8* 160 ± 22* (theobromine)3,9-Dimethyl- 146 ± 26* 141 ± 11* 143 ± 20* xanthine 3-Methylxanthine155 ± 24* 137 ± 10* 134 ± 9* 8-Cyclopentyl-1,3-dimethyl- 155 ± 24* 142 ±14* 133 ± 6* xanthine 7β-Hydroxyethyl-1-1,3-dimethyl- 113 ± 13* 134 ±15* 124 ± 15* xanthine 7-(2,3-Dihydroxypropyl)-1,3-di- 100 ± 16 123 ±16* 117 ± 9* methylxanthine 8-Chloro-1,3-dimethyl-  98 ± 25 108 ± 14 116± 17 xanthine 1,3,9-Trimethyl- 103 ± 18 103 ± 15 105 ± 7 xanthine8-Propionic acid-1,3-dimethyl- 113 ± 13 100 ± 11 102 ± 5 xanthine7,9-Dimethyl-  99 ± 14 100 ± 15 102 ± 13 xanthine 8-Phenyl-1,3-dimethyl-109 ± 11 103 ± 14  99 ± 18 xanthine 7-Acetic acid-1,3-dimethyl-  93 ± 15 99 ± 12  98 ± 19 xanthine 9-Propylxanthine 102 ± 24  97 ± 23  96 ± 129-Methylxanthine  96 ± 11  85 ± 18  98 ± 10 8-Methylxanthine 109 ± 9  90± 11  95 ± 20 8-(p-Sulfophenyl)-1,3-di-  95 ± 7  91 ± 16  92 ± 17methylxanthine 1,9-Dimethyl-  76 ± 13  86 ± 18  84 ± 14 xanthine

[0117] (Specific [³H]ryanodine binding was determined as described inMaterials and Methods in Liu et AL.,Structure-activity Relationship ofXanthines and Skeletal Muscle Ryanodine Receptor/Ca²⁺ Release Channel;Pharmacology1997;54:135-143. Xanthine concentrations were 1.5 mmol/l.Control [³H]ryanodine binding values (-xanthines) were 0.55±0.05,0.73±0.08 and 1.69±0.12 pmol/mg protein in the absence and presence of 3mmol/l AMP or 1 mmol/l AMPPCP, respectively. * Significantly differentfrom control at p<0.05.)

[0118] From the above Table 3 it is seen that nonpolar residues inpositions, 1, 3 and 7 stimulated [³H] ryanodine binding, whereasnonpolar residues in positions 8 and 9 counteracted the effect.

[0119] According to the present invention, substances which have aneffect on the [³H] ryanodine binding of at least 130%, preferable morethan 150% of that of the control xanthine are effective for treating orpreventing disease related to excessive longitudinal growth of the eye,and substances which have an effect on the [³H] ryanodine binding ofless than 130%, preferable less than 100% of that of the control.xanthine are effective for treating or preventing disease ofinsufficient longitudinal growth of the eye.

[0120] According to the present invention, the substances disclosed inTable 3 having the highest binding effect are most preferred fortreating of myopia, such as the substance showing an effect on the [³H]ryanodine binding of more than 200% compared to the control xanthine,and includes the substance Pentifylline. The substances disclosed inTable 3 having the lowest indingeffetare mst preferred for treating ofhypermetropia, such as the substance showing an effect on the [³H]ryanodine binding of less than 110% compared to the control xanthine,and includes the substance 1,9-dimethylxanthine. TABLE 4 Effect ofxanthines on [³H] ryanodine binding to skeletal RyR in the presence of 1mmol/1 AMPPCP Bound [³H] ryanodine pmol/mg % of protein controlMonosubstituted xanthines Control (-xanthine) 1.69 ± 0.12 100 7-Propyl-4.57 ± 0.20 270 ± 12* 3-Propyl- 3.82 ± 0.23 226 ± 14* 7-Methyl- 3.80 ±0.19 225 ± 11 1-Methyl- 3.02 ± 0.38 179 ± 22* 3-Methyl- 2.26 ± 0.15 134± 9* 9-Propyl- 1.62 ± 0.20  96 ± 12 9-Methyl- 1.66 ± 0.17  98 ± 108-Methyl- 1.61 ± 0.33  95 ± 20 Disubstituted xanthines Control(-xanthine) 1.69 ± 0.12 100 1,7-Dimethyl- 6.08 ± 0.47 360 ± 28*3-Butyl-1-methylxanthine 2.96 ± 0.33 175 ± 20* 1,3-Dimethyl- 2.87 ± 0.42170 ± 25* (theophylline) 3,7-Dimethyl-(theobromine) 2.70 ± 0.37 160 ±22* 3,9-Dimethyl- 2.42 ± 0.34 143 ± 20* 7,9-Dimethyl- 1.73 ± 0.22 102 ±13 1,9-Dimethyl- 1.42 ± 0.23  84 ± 14 1-Substituted3,7-dimethylxanthines 3,7-Dimethyl- 2.70 ± 0.37 100 xanthine (control)1-Hexyl-(pentifylline) 6.99 ± 0.80 259 ± 24* 1-Propargyl- 3.88 ± 0.10144 ± 3* 1-(5-Oxohexyl)-(pentoxyfylline) 3.18 ± 0.08 118 ± 3*1-Methyl-(caffeine) 3.07 ± 0.30 114 ± 2 7-Substituted1,3-dimethylxanthines 1,3-Dimethyl- 2.87 ± 0.42 100 xanthine (control)7β-Chloroethyl- 3.88 ± 0.16 135 ± 6* 7-Methyl-(caffeine) 3.07 ± 0.301107 ± 4 7β-Hydroxyethyl- 2.10 ± 0.26  73 ± 4* 7-(2,3-Dihydroxypropyl)-1.97 ± 0.16  69 ± 6* 7-Acetic acid- 1.65 ± 0.32  57 ± 6* 8-Substituted1,3-dimethylxanthines 1,3 Dimethyl- 2.87 ± 0.42 100 xanthine(control)8-Cyclopentyl- 2.25 ± 0.28  78 ± 8 8-Chloro- 1.96 ± 0.13  68 ± 4*8-Propionic acid- 1.73 ± 0.09  60 ± 3* 8-Phenyl- 1.67 ± 0.31  58 ± 9*8-(p-Sulfophenyl)- 1.55 ± 0.28  54 ± 6* Others 1,3-Dipropyl-7-methyl-4.96 ± 0.39 xanthine 1,3,9-Trimethylxanthine 1.77 ± 0.12

[0121] ([³H]ryanodine-binding measurements were determined as describedin Materials and Methods in Liu et AL.,Structure-activity Relationshipof Xanthines and Skeletal Muscle Ryanodine Receptor/Ca²⁺Release Channel;Pharmacology, 1997;54:135-143. Xanthine concentrations were 1.5 mmol/l.The control bound [³H]ryanodine for each subgroup was set equal to 100.Results are means±SD of 3-4 separate experiments. * Significantlydifferent from controls at p<0.05.)

[0122] From this Table 4, the effect of the individual substituents tothe xanthine molecule structure is clearly demonstrated.

[0123] Xanthines which is substituted in one or more of position 1, 3,and 7 (of the general formula of xanthine shown i FIG. 3) with any ofthe following substituents: hydroxy, halogen, triflourmethyl, loweralkyl (C₁₋₆), tertiary amino/alkoxy are preferred for the treatment orprevention of myopia.

[0124] On the other hand, when the xanthine is substituted in one ormore of position 8 and 9 with these substituents, the substance isuseful for treatment or prevention of hypermetropia, especially if thexanthine is only substituted in these positions.

[0125] When the xanthine is substituted in both positions 7 and 9, suchas in 7,9-Dimethylxanthine, the double bond between the nitrogen atomand carbon atom as shown in the general formula (I) is hydrogenated asappears from formula III.

[0126] In the present context, the term “C₁₋₂₀-alkyl” is intended tomean a linear, cyclic or branched hydrocarbon group having 1 to 20carbon atoms, such as methyl, ethyl, propyl, iso-propyl, cyclopropyl,butyl, tert-butyl, iso-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, hexadecyl, heptadecyl, octadecyl, nonadecyl. Analogously,the term “C₁₋₆-alkyl” is intended to mean a linear, cyclic or branchedhydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl,propyl, iso-propyl, pentyl, cyclopentyl, hexyl, cyclohexyl.

[0127] Preferred examples of “C₁₋₆-alkyl” are methyl, ethyl, propyl,iso-propyl, butyl, tert-butyl, iso-butyl, pentyl, cyclopentyl, hexyl,cyclohexyl, in particular methyl, ethyl, propyl, iso-propyl, tert-butyl,iso-butyl and cyclohexyl.

[0128] Similarly, the terms “C₂₋₂₀-alkenyl”, “C₄₋₂₀-alkadienyl”, and“C₆₋₂₀-alkatrienyl” are intended to mean a linear, cyclic or branchedhydrocarbon group having 2 to 20, 4 to 20, and 6 to 20, carbon atoms,respectively, and comprising one, two, and three unsaturated bonds,respectively. Analogously, the term “C₂₋₆-alkenyl” is intended to mean alinear, cyclic or branched hydrocarbon groups having 2 to 6 carbon atomsand comprising one double bond.

[0129] Examples of alkenyl groups are vinyl, allyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl, heptadecaenyl. Examples of alkadienyl groupsare butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadecadienyl.Examples of alkatrienyl groups are hexatrienyl, heptatrienyl,octatrienyl, and heptadecatrienyl.

[0130] The term “C₂₋₂₀-alkynyl” is intended to mean a linear or branchedhydrocarbon group having 2 to 20 carbon atoms and comprising a triplebond. Examples hereof are ethynyl, propynyl, butynyl, octynyl, anddodecaynyl. Analogously, the term “C₂₋₆-alkynyl” is intended to mean alinear or branched hydrocarbon groups having 2 to 6 carbon atoms andcomprising one triple bond, such as ethynyl, propynyl, butynyl,pentynyl, and hexynyl.

[0131] In the present context the term “alkoxy” means alkyl-oxy, and“halogen” means fluoro, chloro, bromo, iodo.

[0132] In the present context, i.e. in connection with the terms “alkyl”, “alkenyl”, “alkadienyl”, “alkatrienyl”, “alkynyl”, and “alk{overscore(o)}xy”, the term “optionally substituted” is intended. to mean that thegroup in question may be substituted one or several times, preferably1-3 times, with group(s) selected from hydroxy (which when bound to anunsaturated carbon atom may be present in the tautomeric keto form),C₁₋₆-alkoxy (i.e. alkyl-oxy), C₂₋₆-alkenyloxy, carboxy, oxo (forming aketo or aldehyde functionality), C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyl, formyl, aryl, aryloxycarbonyl, aryloxy,arylcarbonyl, heteroaryl, heteroaryloxycarbonyl, heteroaryloxy,heteroarylcarbonyl, amino, mono- and di(C₁₋₆-alkyl)amino; carbamoyl,mono- and di-(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, guanidino, carbamido, C₁₋₆-alkanoyloxy,sulphono, C₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, C₁₋₆-alkylthio,trihalogen-C₁₋₆-alkyl, halogen such as fluoro, chloro, bromo or iodo,where aryl and heteroaryl may be substituted as specifically describedbelow for “optionally substituted aryl and heteroaryl”.

[0133] In the present context the term “aryl” is intended to mean afully or partially arormatic carbocyclic ring or ring system, such asphenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl,pyrenyl,-benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is apreferred example.

[0134] The term “heteroaryl” is intended to mean a fully or partiallyaromatic carbocyclic ring or ring system where one or more of the carbonatoms have been replaced with heteroatoms, e.g. nitrogen, sulphur,and/or oxygen atoms. Examples of such heteroaryl groups are oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl,pyridinyl, pyrazinyl, pyridazinyl, piperidinyl, coumaryl, furyl,quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl,phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl,carbazolyi, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl.Preferred hete.roaryl groups are pyridinyl, benzopyrazolyl, andimidazolyl.

[0135] In the present context, i.e. in connection with the terms “aryl”and “heteroaryl”, the term “optionally substituted” is intended to meanthat the group in question may be substituted one or several times,preferably 1-5 times, in particular 1-3 times) with group(s) selectedfrom hydroxy (which when present in an enol system may be represented inthe tautomeric keto form), C₁₋₆-alkyl, C₁₋₆-alkoxy, oxo (which may berepresented in the tautomeric enol form), carboxy, C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyl, formyl, aryl, aryloxy, aryloxycarbonyl,arylcarbonyl, heteroaryl, amino, mono- and di(C₁₋₆-alkyl)amino;carbamoyl, mono- and di(C₁₋₆-alkyl)amino-carbonyl,amino-C₁₋₆-alkyl-anocarbonyl, mono-and-di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, guanidino, carbamido, C₁₋₆-alkanoyloxy,sulphono, C₁₋₆-alkyl-sulphonyloxy, nitro, sulphanyl,dihalogen-C₁l₄-alkyl, -trihalogen-C₁₋₆-alkyl, halogen such as fluoro,chloro, bromo or iodo, where aryl and heteroaryl representingsubstituents may be. Preferred examples are hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, carboxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl, aryl,amino, mono- and di(C₁₋₆-alkyl)amino, and halogen such as fluoro,chloro, bromo or iodo, wherein aryl and heteroaryl may be substituted asabove.

[0136] The pharmaceutical preparation according to the present inventionmay be formulated in accordance with conventional pharmaceuticalpractice with pharmaceutical excipients conventionally used for thepreparation of oral, topical and systemical formulations. In addition,many of the substances are well known medical formulations.

[0137] The concentration of the substance or mixture of substances maybe present in the medicament in an amount of 0.001-99%, typically0.01-75%, more typically 0.1-20%, especially 1-10% by weight of themedicament, however, for many of the substances are already avaible forpharmaceutical use, and generally, the substances are then to be used inordinary clinical dosageg and concentrations known in the litterature.

[0138] In another aspect of the invention, the dosage is correlated toan effect similar to the eeffect of the testes drugs of the presentinvention and which appears from the examples. This correlation may beperformed by the measuring methods as described en the present text.

[0139] The preparation of the invention may also contain other additivessuch as emulsifieres, stabilizing agents, preservatives, etc.

[0140] The invention is furthermore described in the claims and renderedprobable in the following examples.

[0141] List of Examples

[0142] Example 1 Materials and Methods

[0143] Example 2 Biochemical changes in rabbit sclera after long termtreatment with Fluoxetine, Teofylamin, Caffeine and L-cysteine.

[0144] Example 3 Effect of myopia progression in a human by treat mentwith caffeine and L-cysteine.

[0145] Example 4 Biochemical changes in rabbit sclera after longtermtreatment with 7-methylxanthine, Theobromine, Acetazolamide,; andL-ornithine.

[0146] Example 5 Effect on proteoglycanes compared with effect on [³H]ryanodine binding of different xanthines.

[0147] Example 6 Extraction method for substance from natural source.

[0148] Example 7 Extraction method for substance from natural source.

[0149] Example 8 Experiments under investigation

[0150] Comments to the Examples

[0151] On the basis of the biochemical results in Example 2 it is likelythat a treatment of myopia with caffeine will be more efficient thanL-cystine as a moderate dosage of caffeine unambiguously affects allparameters appropriately.

[0152] In humans caffeine has a relatively long half-life period(approximately 5 hours). After administration of a dosage of caffeine,the serum concentration of caffeine is therefore dominant, however, withan essential contribution of the pharmacologically active metabolites1,7-dimethylxanthine (paraxanthine), 3,7-dimethylxanthine (theobromine),and 1,3-dimethylxanthine (theophylline), 1-methylxanthine,3-methylxanthine, and 7-methylxanthine (heteroxanthine).

[0153] In rabbits the half-life period for caffeine is short(approximately 1 hour) and the most essential contribution for the serumcomes from te metabolite 1,7-dimethylxanthine whereas the serumconcentration of caffeine will be esbentially lower.

[0154] The strong effect of caffeine on the biochemical composition ofsclera, as it appears from Example 2, is believed to be due to theabove-mentioned metabolites of caffeine.

[0155] Example 3 demonstrates that substances identified according toExample 2 of having specific effects on the biochemical composition ofsclera of a non-human mammal, the rabbit, in fact are able to preventinappropriate growth of the eye, in a human.

[0156] Example 4 shows that the caffeine metabolite theophylline(1,3-dimethylxanthine) partly reduces c-wave at ERG and the standingpotential of the eye, and partly reduces the content of proteoglycanesin sclera. Theophylline does increase the content of the collagenspecific amino acids hydroxyproline and proline, but it reduces thecontent of hydroxylysine. In total theophylline therefore has aninhibiting effect on the content of connective tissue components andthus a directly opposite effect as compared to the closely familiarsubstance caffeine.

[0157] Caffeine is transformed,after administration partly totheophylline which works against the stimulatingeffect of caffeine onthe scleral tissue. In order to avoid this weakening effect thosemetabolites can be employed for caffeine which is not transformed intotheophylline.

[0158] Theophylline only differs from caffeine by not having a 7-methylgroup. Other appropriate substances for treatment of myopia amongcaffeine derivatives or analogues with a 7-methyl group include.1,7-dimethylxanthine (paraxanthine), and 7-methylxanthine(heteroxanthine) are especially interesting, however also3-methylxanthine and 1-methylxanthine are believed to be effectiveagainst myopia.

[0159] Other 7-methyl xanthines which can be effective for treatment ofmyopia can involve derivatives of xanthine having substituents in otherpositions than the 7-position. In a similar way, xanthines derivativesnot having a methyl group in the 7-position may be useful for thetreatment of hypermetropia.

EXAMPLE 1

[0160] Materials and Methods

[0161] Test animal: Charles River Deutschland Chinchilla Bastard femalerabbits.

[0162] Number of animals: 6 test animals and 6 control animals

[0163] Age: approximately 8 weeks at the commencement of the test.

[0164] Weight: 1.4-1.9 kg at the commencement of the test.

[0165] Lightness/Darkness cycle: 12/12 hours.

[0166] Water: ad libitum.

[0167] Cages: The animals live in identical cages made of stainlesssteel-(Scanbur), length 1 m, depth 0.52 m, height 0.5 m.

[0168] Food: Stanrab standard diet from Special Diet Services, P.O. Box705, Witham Essex CM8 3AD, UK (further details, see Table A).

[0169] Amount of food: Increasing from 75 g per day at the commencementof the test up to 130 g after three months.

[0170] Experimental drinking water 1 contained theophyllin in a doseequivalent of 27 mg increasing to 63 mg (added as theophyllin andethylendiamin in a dose of 33 to 77 mg) daily.

[0171] Experimental drinking water 2 contained fluoxetine (Fontex,Lilly) in a dose equivalent of 2 mg increasing to 5 mg daily.

[0172] Experimental diet 1 was added caffeine (1,3,7-trimethylxanthine)500 mg per kg Stanrab standard diet equivalent of a daily caffeine doseof 37.5 g increasing to 65 g per day.

[0173] Experimental diet 2 was added 4.5 g L-cystine per kg Stanrabstandard diet equivalent of a daily L-cystine dose of 338 mg increasingto 585 mg per day. With respect to the supplement of L-cystine, thenormal intake per day of the standard diet is 218 mg increasing to 377mg L-cystine.

[0174] Experimental diet 3 was added 7-methylxanthine 500 mg per kgStanrab standard diet equivalent of a daily 7-methylxanthine dose of37.5 g increasing to 65 g per day.

[0175] Experimental diet 4 was added theobromine (3,7-dimethylxanthine)500 mg per kg Stanrab standard diet equivalent of a daily theobrominedose of 37.5 g increasing to 65 g per day.

[0176] Experimental diet 5 was added acetazolamide 500 mg per kg Stanrabstandard diet equivalent of a daily acetazolamide dose of 37.5 gincreasing to 65 g per day.

[0177] Experimental diet 6 was added 4.5 g L-ornithine per kg Stanrabstandard diet equivalent of a daily L-ornithine dose of 338 mgincreasing to 585 mg per day.

[0178] Collection of sample: Sclera biopsies are taken for analysis forproteoglycane content, distribution between the individualglycosaminoglycanes and the content of collagen specific amino acids.Four tests from each animal: Two samples from the front, 5×10 mm alonglimbus (without cornea), and two samples from the back, punch 10 mmcorresponding to the center of the retina. Furthermore, tests are takenfor electron microscopy (EM) from two animals in each group.

[0179] Analyses: Samples for proteoglycane analysis are frozen downimmediately. The samples are analyzed by Wieslab AB, IDEON, S-223 70Lund, Sweden, by means of a method which has been described byBjörnsson, S., Analytical Biochemistry 210, 282-291 (1993). The methodcomprises extraction by 20 microlitres of 4 M guanidine-HCl, 50 Mmsodium acetate per mg wet weight over night by room temperatures. Theextracts are centrifuged in order to remove debris. 20 microlitres ofsupernatant are reduced {fraction (1/10)} in extraction buffer and 20microlitres of reduced supernatant are mixed with 10 microlitres ofreagent 1 (see Björnsson, S., Analytical biochemistry 210, 282-291(1993)) on a shaking table for 15 minutes. 200 microlitres of reagent 2are added and the tests are incubated for 60 minutes in order toprecipitate the proteoglycanes. The proteoglycane/alcian blueprecipitate is transferred to 96-wells MillBlotD apparatus and washedwith 2×200 microlitres of 40% DMSO, 0.05 M of MgCl₂. The colourintensity of the wells are quantitated by microtech E3 scanner and ScanAnalysis software (Biosoft, Cambridge, U.K.). Chrondroitine-6-sulphate(Sigma C4384) is used as the calibrator. All samples are analyzed induplicate.

[0180] Samples for analysis for content of collagen specific amino acidsare frozen down immediately. The amino acid content is determined byHPLC-chromatography. The tissue bits are delipidized with acetone at 4°C. in 3×24 hours, then with acetone:diethylether 1:1 for 24 hours, andfinally 1 hour of standing with pure diethylether.

[0181] Then they are dried to constant weight by standing in vacuumexsiccator for 1.5 hours with the pump on and after closure standingover night.

[0182] The dried tissue with constant weight is minced into very fineparticles with a pair of scissors, approximately 20 per piece of tissue.The small flakes from each original piece of tissue are divided into twoequally sized portions, one of which is employed for hydrolysis and theother one is kept for reference. The constant dry weight of each portionis known.

[0183] The finely divided tissue is hydrolyzed in Pyrex glass tube s for24 hours at 114° C., and subsequently the hydrolysates are dried(removal of remnants from of hydrochloric acid) by standing in vacuumexsiccator at 40° C. over night. The dry residue of hydrolysate isresolubilized in 320 microliter of 0.1N hydrochloric acid by standing inultrasound bath for 10 minutes vortexing and then standing over night at4° C. surrendered by a final wortexing and centrifugation.

[0184] From each resolubilized hydrolysate 3 aliquots of each 8microlitres and 3 aliquots of 40 μl are taken and transferred toseparate polypropylene tubes in which 20 microlitres of a solution ofinternal standard substances citrulline and 2 aminobutyric acid wereadded where the further method takes place.

[0185] The taken aliquots from hydrolysate are dried in a vacuumexsiccator at 35° C. over night and subsequently submitted toderivatization with phenylisothiocyanate.

[0186] The resulting phenylisothiocarbamates are transferred to the HPLCinstrument for separation and quantification. A new set of calibrationcurves is established, 1 curve for each of the 19 amino acids, prior tothe analysis of the samples from one investigation.

[0187] The concentration range of standard samples exceed the ranges ofamino acid concentrations in the unknowns. Hydroxyproline and prolineare quantitated from the 8 microliter aliquots, and hydroxylysine isquantitated from the 40 microliter aliquots.

[0188] The curves were straight with a high coefficient of correlation.

[0189] Samples for analysis of the distribution between the variousglycosaminoglycanes are immediately put in acetone. The analysis is madewith a method described by Olsen, E. B., Acta Orthop. Scand. 60 (1),23-25 (1989), comprising delipidization, drying, digestion with pronase.The glycosaminoglycanes are seperated in the procedure comprisingcentyltrimethyl ammonium bromide. The glycosam centyltrimethyl ammoniumbromide complex is washed with ethanol saturated with NaCl in order toremove centyltrimethyle ammonium bromide. The cleanedNa-glycosaminoglycanes are dried and resolubilized in NaOH and distilledwater for further analysis. The individual glycosaminoglycanes areseparated by means of cellulose acetate electroforese, and the relativecontent of the essential glycosaminoglycanes are measured by means ofoptical scanning.

[0190] EM is made on ultra thin cuts from the center part of thebiopsies after fixation in 4% of glutaraldehyde in caccodylate bufferwith 7.5% sucrose at 40° C. over night, dehydrated in ethanol andmoulded in epoxy resin. The cuts are stained with saturated uranylacetate solution in 50% of ethanol for 1 hour, followed by lead citrate(Reynolds) for 3 minutes for routine electron microscopy.

[0191] Ultra thin cuts are collected on gold nets and stained by meansof periodine acid-silver proteinate technique for glucoproteins (PAS)and with 0.1% of ruthenium red solution in 0.1 M ammonia for acidicglycosaminoglycanes. The results of longterm treatment with each of the8 substances specified above are shown in Example 2 (treatment for 12weeks) and Example 4 (treatment for 10 weeks).

[0192] No significant differences between control and treatment groupswas identif ed with respect to bodyweight and weight of eyes.

EXAMPLE 2

[0193] Long time treatment of 3 month with each of the four substances,Caffeine, L-cysteine, Teofylamin, and Fluoxetine and the effect on thebiochemical changes in rabbit sclera TABLE 5 Content of collagenspecific amino acicis in nanomol/mg tissue (dried weight defattedweight) from anterior sclera (Wilcoxon test. *p < 0.05), and theincrease (Inc.) or decrease (Decr.) compared to the control.Hydroxyproline Hydroxylysine Proline Control 604 +/− 50 41 +/− 12 886+/− 29 Fluoxetine 619 +/− 40 33 +/− 11 896 +/− 21 Teofylamin 653 +/− 3928 +/− 10 958 +/− 23 Caffeine  688 +/− 36* 39 +/− 19  993 +/− 18*L-cystine 599 +/− 41 45 +/− 10 885 +/− 22 Hydroxyproline HydroxylysineProline Inc. Decr. Inc. Decr. Inc. Decr. Fluoxetine — — — 20% — —Teofylamin  8% — — 32%  8% — Caffeine 14% — — — 12% — L-cystine — — — —— —

[0194] TABLE 6 Content of collagen specific amino acids in nanomol/mgtissue (dried weight and defatted weight) from posterior sclera(Wilcoxon test.), and the increase (Inc.) or decrease (Decr.) comparedto the control. Hydroxyproline Hydroxylysine Proline Control  547 +/−141 43 +/− 12 810 +− /86 Fluoxetine 640 +/− 31 41 +/− 13 927 +/− 15Teofylamin 643 +/− 74 28 +/− 15 902 +/− 53 Caffeine 668 +/− 61 37 +/− 16947 +/− 38 L-cystine 596 +/− 39 43 +/− 8  867 +/− 14 HydroxyprolineHydroxylysine Proline Inc. Decr. Inc. Decr. Inc. Decr. Fluoxetine 17% —— — 15% — Teofylamin 18% — — 35% 11% — Caffeine 22% — — 14% 17% —L-cystine  9% — — —  7% —

[0195] TABLE 7 Content of proteoglycanes in μg PG/mg tissue (wet weight)(Wilcoxon test. *p < 0.05), and the increase or decrease compared to thecontrol. Anterior sclera Posterior sclera Control 2.7 +/− 0.2 2.7 +/−0.2 Fluoxetine  2.2 +/− 0.4* 2.6 +/− 0.2 Teofylamin 2.4 +/− 0.5 2.7 +/−0.3 Caffeine 3.2 +/− 0.8 3.2 +/− 0.5 L-cystine  3.5 +/− 0.5*  3.5 +/−0.4* Anterior sclera Posterior sclera Increase Decrease IncreaseDecrease Fluoxetine — 19% — — Teofylamin — 11% — — Caffeine 19% — 19% —L-Cystine 29% — 29% —

[0196] Conclusion:

[0197] Fluoxetine: Treatment with fluoxetine (a serotonin re-uptakeinhibitor) for three months decreased the content of proteoglycanes inanterior sclera by 19%. Hydroxylysine in the anterior sclera isdecreased with 20% and hydroxyproline and proline are increased with 17%and 15%, respectively, in the posterior sclera.

[0198] Teofylamin: Treatment with Teofylamin for 3 months reduces thecontent of proteoglycanes in sclera by 11% (at the front).

[0199] Caffeine: Treatment with caffeine for three months increases thecontent of proteoglycanes in sclera by 19% (to the front) and 19% (tothe back). The content of the collagen specific amino acidshydroxyproline and proline are increased by 22% and 17%, respectively,in sclera tests in the back of the eye. Accordingly, the example showsthat treatment or a young mammal with caffeine in a moderate dosageresults in a strong increase in the content of proteoglycanes as well asin collagen specific amino acids in sclera.

[0200] L-cystine: Treatment of young rabbits for three months withL-cystine increases the content of proteoglycanes in the sclera by 29%in both the front and in the back of eye. The content of the collagenspecific amino acids hydroxyproline and proline are increased by 9% and7%, respectively, in sclera samples from the back of the eye.Accordingly, the example shows that treatment with a relative largedosage of L-cystine also increases the content of proteoglycanes, butthat the effect on the content of collagen specific amino acids isambiguous.

EXAMPLE 3

[0201] Myopia progression stopped by treatment with caffeine andL-cystine

[0202] A boy presented with myopia at the age of 9 years. Earlierexamination showed no ametropia. He had severely progrediating myopiaand was treated with a combination of caffeine (100 mg/day) andL-cystine (200 mg/day) for three months followed by a control period ofthree months with no treatment, and subsequently a new treatment periodfollowed by a control period, etc. In total 4-treatment periods and 4control periods alternated.

[0203] Measurement of the axial length of the eye was made by means ofAuto Axial Biometer AL-010, Shin-Nippon.

[0204] Table 8 and Table 9 shows the average growth in the axial lengthof both eyes in the 4 treatment periods and the 4 control periods,respectively. TABLE 8 Treatment with caffeine 50 mg × 2 and L-cystine100 mg × 2 (tablets) from day 0-90, day 161-289, and 412-570. Day RE LE0 23.74 23.70 57 23.86 23.58 118 24.06 23.83 161 24.14 24.07 227 24.2124.03 260 24.26 24.10 289 24.24 24.22 350 24.43 24.44 392 24.56 24.47412 24.59 24.39 447 24.63 24.53 476 24.73 24.52 503 24.74 24.53 54124.72 24.49 570 24.71 24.55

[0205] TABLE 9 Average growth during treatment and control periods,respectively. Axial length growth n Caffeine + L-cysteine 0.089 mm 4(100 + 200 mg/day) Control period 0.253 mm 4

[0206] Conclusion: Example 3 confirms that treatment with a combinationof caffeine and L-cystine actually is able to inhibit the myopiaprogression in a child as a significant effect of the treatment with afactor of 3 (inhibition of growth) in relation to no treatment isdemonstrated in study.

EXAMPLE 4

[0207] The Effect of the Caffeine Metabolite 7-methylxanthine(heteroxanthine) 50 mg per Animal Daily on Scleras Content ofProteoglycanes and Collagen Specific Amino Acids

[0208] The effect of the caffeine metabolite 3,7-dimethylxanthine(theobromine) 50 mg per animal daily on scleras content ofproteoglycanes and collagen specific amino acids.

[0209] The effect of acetazolamide 50 mg per animal daily on sclerascontent of proteoglycanes and collagen specific amino acids.

[0210] The effect of 500 mg per animal daily of L-ornithine on sclerascontent of proteoglycanes and collagen specific amino acids.

[0211] Conclusion: No significant differences were found as regards thecontent of proteoglycans in the sclera samples, but there was a nearsignificant increase in 7-methylxanthine treated posterior sclera, and adecrease in theobromine treated posterior sclera.

[0212] Significant higher content of all collagen specific amino acids,except hydroxylysine in anterior sciera, was found in all sclera samplesfrom theobromine (3,7-dimethylxanthine) treated animals. Animals treatedwith 7-methylxanthine showed significantly higher content ofhydroxyproline and proline in posterior sclera. Treatment withacetazolamide reduced the content of hydroxyproline and proline inanterior sclera significantly. TABLE 10 Content of proteoglycanes in μgPG/mg tissue (wet weight) anterior sclera posterior sclera Control 2.9+/− 0.5 2.9 +/− 0.4 7-methyixanthine 2.5 +/− 0.5 3.3 +/− 0.33,7-dimethyixanthine 2.6 +/− 0.7 2.5 +/− 0.4 Acetazolamide 2.9 +/− 0.42.8 +/− 0.8 L-ornithine 3.0 +/− 1.1 3.0 +/− 0.9 Anterior scleraPosterior sclera Increase Decrease Increase Decrease 7-methylxanthine —14% 14% — 3,7-dimethylxanthine — 10% — 14% Acetazolamide — — — —L-ornithine — — — —

[0213] TABLE 11 Content of collagen specific amino acids in nanomol/mgtissue (dried weight defatted weight) from anterior sclera. (Wilcoxontest. *p < 0.05) Hydroxyproline Hydroxylysine Proline Control 638 +/− 24 45 +/− 10 928 +/− 56 7-methylxanthine 667 +/− 73 45 +/− 3  951 +/− 1113,7-dimethylxanthine  751 +/− 53* 49 +/− 6 1073 +/− 78* Acetazolamide 596 +/− 27* 41 +/− 4  843 +/− 47* L-ornithine 605 +/− 37 37 +/− 4 875+/− 48

[0214] TABLE 12 Content of collagen specific amino acids in nanomol/mgtissue dried weight and defatted weight) from posterior sclera.(Wilcoxon test. *p < 0.05) Hydroxyproline Hydroxylysine Proline Control622 +/− 59 41 +/− 5 864 +/− 67 7-methylxanthine  719 +/− 81* 44 +/− 7 1018 +/− 108* 3,7-dimethylxanth.  741 +/− 18*  49 +/− 4* 1029 +/− 45*Acetazolamide 563 +/− 91 38 +/− 6  781 +/− 125 L-ornithine 611 +/− 24 38+/− 5 871 +/− 35 Hydroxyproline Hydroxylysine Proline Inc. Decr. Inc.Decr. Inc. Decr. 7-methylxanthine 16% — 7% — 10% — 3,7-dimethylxanth.19% — 20% — 20% — Acetazolamide — 10% — 7% — 10% L-ornithine — — — 7% ——

EXAMPLE 5

[0215] Effect on Proteoglycanes Compared with Effect on [³H RyanodineBinding of Different Xanthines

[0216] Comparison of effect on proteoglycanes content of posteriorsclera in % to control with effect on [³H ryanodine binding in %compared to control. TABLE 13 Effect on proteoglycan Effect on [³Hcontent of posterior ryanodine binding sclera in % in % comparedcompared to control to control Caffeine 119 240 Theophylline 100 1367-methylxanthine 114 204 Theobromine 86 124

EXAMPLE 6

[0217] Extraction Method

[0218] The plant material must either be extracted immediately afterharvesting or stored at −20° C. until extraction take place, andpreferable, the material is freeze-dried before the cold storage. Thematerial is finely ground and boiled for 20 minutes with 0.0125 Nsulphuric acid. After cooling the extract is applied to a column packedwith siliceous earth (Extralut, Merck), 700 p per litre of extract, andafter 10 minutes the column is eluted with a 4-fold volume ofchloroform. The chloroform phase is eluted to dryness and chloroformcondensed and collected for re-use. The residue contains themethylxanthines.

EXAMPLE 7

[0219] The plant material must either be extracted immediately afterharvesting or stored at −20° C. until extraction can take place, andpreferable, the material must be freeze-dried before the cold storage.The material is finely ground and boiled for 20 minutes with =0.1Nhydrochloric acid. After cooling the extract is filtered and applied toa column packed with polyvinylpyrrolidone powder, and after 10 minutesthe column is eluted with water. The fraction of the eluate which has ahigh concentration of the methylxanthine in question is collected andevaporated to a standardized concentration of this substance.

EXAMPLE 8

[0220] Experiments under investigation:

[0221] A) The effect of the Caffeine metabolite 3,7-dimethylxanthine(theobromine) on c-wave by ERG and the standing potential of the eye isunder investigation.

[0222] B) The effect of the caffeine metabolite 7-methylxanthine(heteroxanthine) on c-wave by ERG and the standing potential of the eyeis under investigation.

[0223] C) Pilot projects

[0224] Substances to be tested for treatment or preventing of myopia:

[0225] 1) Caffeine and L-cystine (dosages as described)

[0226] 2) 7-methylxanthine 250 mg

[0227] 3) Pentifylline 250 mg Substances to be tested for treatment orpreventing of hypermetropia:

[0228] 4) 1,9-dimethylxanthine 250 mg

[0229] 5) theobromine 250 mg (may be used once or twice daily equivalentof 10 or 20 mg per kg per day with a body weight of 25 kg)

[0230] The Test conditions:

[0231] Caffeine and L-cystine are to be given as tablets for theinhibition of the progression of myopia in a group of children aged10-14.

[0232] The Background of the Test

[0233] The content of L-cystine in the food varies depending on whetherthe protein need is covered by e.g. fish (approximately 350 mg L-cystineper day for a child weighing 30 kg) or wheat bread (approximately 700 mgL-cystine per day) (Garrow, J. S.: Human Nutrition and Dietetics,Churchill Livingstone, 1993). L-cystine is absorbed through theintestine, the part that is not used for the building up of the proteinsof the body is burnt on equal terms with e.g. sugar.

[0234] Caffeine is a well-known, component of e.g. coffee, tea,chocolate and cola soft drinks. One cup of coffee contains 100-150 mg ofcaffeine, one cup of tea approximately 60 mg, one cup of cocoaapproximately 5 mg, and one glass of cola approximately 20 mg. Only avery small part of the caffeine in cola comes from the cola nut,primarily it is a matter of added caffeine. Thus it has been calculatedthat the total consumption of caffeine in cola in the U.S.A. correspondsto the amount deriving by way of decaffeinating coffee in the country(James, J. E.: Caffeine and Health, Academic Press, 1991).

[0235] From the above foods children in the U.S.A. aged 10-17 consumeapproximately 1.5 mg of caffeine per kg weight per day, i.e. for a childof 30 kg approximately 45 mg per day (Albeit, M. L.: Journal of theAmerican Dietetic Association, 88, 466-471 (1988). A Finnish examinationshowed that approximately 40% of children aged 12 consumed one or morecups of coffee per day. An even larger percentage consumed tea or hotchocolate every day (55<, E.: Social Science and Medicine, 26, 259-264(1988).

[0236] L-cystine is an important factor in the stabilisation of thecollagen molecules in the sclera as it forms the basis of sulphurouscross-links. Therefore, it is possible that, in a period with heavy bodyweight increase, a relative lack of L-cystine can lead to an unstablecollagen and thus participate in developing myopia.

[0237] Therefore it is possible that supplementing the diet withL-cystine can inhibit the development of myopia.

[0238] Candidates of substances applicable for treatment of such arelatively benign condition as myopia in so many children mustnecessarily be free of almost any side effects.

[0239] Caffeine and L-cystine comply with. this condition. Treating a9-year old boy with severely increasing myopia (Example 3) also impliesan effect as the axial longitudinal growth over a period of three monthswas reduced from 0.253 mm to 0.089 mm with caffeine 100 mg +L-cystine200 mg per day. The treatment showed no side effects.

[0240] The normal longitudinal growth of the human eye for the age of3-14 amounts to approximately 0.1 mm per year, but there is muchvariation. In approximately 15% the axial longitudinal growth isthus >0.4 mm per year (Sorsby, A., Med. Res. Counc. Spec. Rep. Ser., No.301, London, 1962). Particularly this group develops myopia.

[0241] c. Test persons

[0242] Boys and girls aged 10-14 with progreding myopia.

[0243] Inclusion: 3×12 myopic persons, 10-14 years old, glass strength>−1.25.

[0244] Exclusion: Severe ordinary disease (e.g. asthma, epilepsy,diabetes, physical disease), severe congenital myopia other severe eyediseases (e.g. congenital cataract, ceratoconus, chronic iritis,glaucoma).

[0245] The test persons were recruited from practising ophthalmologists.

[0246] As myopia develops in the childhood it is necessary to applychildren in the test.

[0247] e. Method

[0248] Pilot test.

[0249] 12 persons are treated with tablets of caffeine, 50 mg in themorning and 50 mg in the evening for 6 months.

[0250] 12 persons are treated with tablets of L-cystine, 100 mg in themorning and 100 mg in the evening for 6 months.

[0251] 12 persons are treated with tablets of caffeine, 50 mg, andtablets of cystine, 100 mg in the morning and in the evening for 6months.

[0252] Then a control period of 6 months follows with no treatment. Thelevel of myopia progression for the two periods is compared for eachparticipant.

[0253] Furthermore, the myopia progression in the treatment period iscompared with existing material concerning myopia progression inchildren of the same age group (e.g. Jensen, H.: Myopia progression inyoung school children, Acta Ophthal., Suppl. 200, Vol 69, 1991).

[0254] During the test the following examinations are made:

[0255] 1. Statup at the commencement of the test.

[0256] a. Subjective measuring of glass strength (ordinary glassdetermination)

[0257] b. Refraction determination with auto refractor (objectivedetermination of the glass strength) in cyclogylcycloplegy (cancellingthe accommodation reflex with cyclogyl drops).

[0258] c. Measuring the axial length with Shin-Nippon axial lengthmeasurer. The patient is dripped with local anaesteticum, and an ultrasound probe is put on the eye by means of a tonometer set at 15 mmHg.The axial length is stated in mm by the apparatus by 2 digits.

[0259] Three measurements are made and the average is calculated.

[0260] 2. Measurement of the axial length after two months (as 1c).

[0261] 3. Measurement of the axial length after 4 months (as 1c).

[0262] 4. Status after 6 months (as 1a-c).

[0263] 5. Measurement of the axial length after 8 months (as 1c).

[0264] 6. Measurement of the axial length after 10 months (as 1c).

[0265] 7. Status after 12 months (as 1a-c).

[0266] Data identifying the patient is destroyed at the end of the test.TABLE A STANDARD RABBIT DIET (STANRAB) Crude Oil % 3.1 Glycine % 1.39Crude Protein % 16.7 Aspartic acid % 1.14 Crude Fibre % 14.8 Glutainicacid % 3.01 Ash % 8.1 Proline % 1.18 N.F.E. % 47.3 Serine % 0.70 Dig,Crude Oil % 2.8 Hydroxyproline % — Dig, Crude % 14.9 Hydroxylysine % —Protein Tot, Dietary % 31.9 Alanine % 0.11 Fibre Pectin % 2.4 Calcium %0.83 Hemicellulose % 14.7 Total Phosphorous % 0.61 Cellulose % 11.7Phytate % 0.36 Phosphorous Lignin % 3.1 Available % 0.25 PhosphorousStarches % 22.7 Sodium % 0.25 Sugars % 7.5 Chlorine % 0.36 Gross Energymj/k 14.8 Magnesium % 0.41 Dig, Energy mj/k 9.1 Potassium % 1.52 Met,Energy mj/k 8.2 Iron mg/kg 194.0 Myrletoleic % 0.02 Copper mg/kg 17.0acid Palmitoileic % 0.09 Manganese mg/kg 93.0 acid Oleic acid % 0.79Zinc mg/kg 47.0 Linoleic acid % 0.75 Cobalt mcg/kg 535.0 Linolenic acid% 0.18 Iodine mcg/kg 665.0 Arachidonic % 0.15 Selenium mcg/kg 217.0 acidClupanodonic % — Fluorine mg/kg 24.0 acid Lauric acid % 0.03 Retinolmcg/kg 47473.0 Myristic acid % 0.18 Vitamin A iu/kg 156991.0 Palmiticacid % 0.37 Cholecalciferol mcg/kg 37.6 Stearic acid % 0.07 Vitamin D3iu/kg 1504.0 Arginine % 1.21 α-Tocopherol mg/kg 62.0 Lysine % 0.91Vitamin E mg/kg 68.2 Methionine % 0.35 Vitamin B1 mg/kg 10.6 Cystine %0.29 Vitamin B2 mg/kg 14.2 Tryptophan % 0.28 Vitamin B6 mg/kg 7.6Histidine % 0.44 Vitamin B12 mcg/kg 11.0 Threonine % 0.68 Vitamin Cmg/kg 113.0 Isoleucine % 0.74 Vitamin K3 mg/kg 63.2 Leucine % 1.28 Folicacid mg/kg 2.1 Phenylalanine % 0.82 Nicotinic acid mg/kg 73.8 Valine %0.88 Pantothenic mg/kg 34.7 acid Tyrosine % 0.62 Choline mg/kg 1151.0Taurine % — Inositol mg/kg 1515.0 Biotin mcg/kg 344.0 p-aminobenzoicmg/kg — acid β-Carotene mg/kg 99.2 Xanthophyl mg/kg —

1. A method for screening substances effective of treating or preventingdisorders of the eye related to the axial length of the eye comprisingidentifying substances based on an effect by the substance on theretinal pigment epithelium of an eye.
 2. The method according to claim 1further comprising administering the substance to an individual andmeasuring the effect of the substance on the retinal pigment epitheliumof the individual upon administration.
 3. The method according to claim1 comprising administering the substance to an in vitro preparation ofretinal pigment epithelium and measuring the effect of the substance onthe retinal pigment epithelium therein.
 4. The method according to anyof claims 1 and 2 wherein the effect on the retinal pigment epitheliumis through an effect of the substance on the neuroretina.
 5. The methodaccording to any of claims 1 and 2 wherein the substance further has aneffect on the neuroretina.
 6. The method according to claim 5 whereinthe effect on the neuroretina also induces an effect on the retinalpigment epithelium.
 7. The method according to any of the precedingclaims wherein the effect on the retinal pigment epithelium is on theion exchange over the cell membrane of the retinal epithelium such as onthe Ca²⁺ exchange, e.g. through the receptors ryanodine receptor (RyR)and/or on the inositol trisphosphate (IP₃) receptor.
 8. The methodaccording to any of the preceding claims wherein the effect on theretinal pigment epithelium is a metabolic effect.
 9. The methodaccording to any of the preceding claims wherein the effect on theretinal pigment epithelium is an effect substantially directly on theretinal pigment epithelium compared to an effect through an effect onthe neuroretina.
 10. The method according to any of the preceding claimswherein the effect of the substance on the retinal pigment epithelium ismeasured by means of the standing potential and/or on the amplitude ofthe c-wave by electro retinography (ERG).
 11. The method according toany of claims 9 and 10 wherein the effect on the retinal pigmentepithelium is measured by means of the amplitude of the c-wave byelectro retinography (ERG) and the effect on the neuroretina is measuredby means of the amplitude of the a-wave and/or b-wave by electroretinography (ERG) upon administration of the substance.
 12. The methodaccording to any of the preceding claims wherein the substanceincreases, upon administration or application of the substance, thestanding potential and/or the amplitude of the c-wave measured byelectro retinography (ERG) and/or increases ryanodine receptor (RyR)and/or inositol trisphosphate (IP₃) receptor binding.
 13. The methodaccording to claim 12 for identifying substances effective of inhibitingthe longtitudinal growth of the eye.
 14. The method according to claim13 for identifying substances for the treatment or prevention of myopia.15. The method according to any of claims 1-11 wherein the substancedecreases, upon administration or application of the substance, thestanding potential and/or the amplitude of the c-wave measured byelectro retinography (ERG) and/or decreases ryanodine receptor (RyR)and/or inositol trisphosphate (IP₃) receptor binding.
 16. The methodaccording to claim 15 for identifying substances effective of increasingthe longtitudinal growth of the eye.
 17. The method according to claim16 for identifying substance for the treatment of hypermetropia.
 18. Themethod according to any of claims 12 and 15 wherein the increase ordecrease, respectively, corresponds to at least 10% compared to theinitial value, such as at least 20%, preferable at least 25%.
 19. Themethod according to any of the preceeding claims wherein the substanceis a mixture of two or more substances.
 20. A method for screeningsubstances effective of preventing or treating disorders of the eyerelated to the axial length of the eye comprising identifying substanceshaving an effect on the composition of the proteoglycanes and/or thecollagen specific amino acid present in the connective tissue of thesclera of the eye.
 21. The method according to claim 20 comprisingadministering the substance to an animal and measuring the effect on thecomposition of the proteoglycanes and/or the collagen specific aminoacid present in the connective tissue of the sclera upon administration.22. The method according to claim 20 comprising administering thesubstance to an in vitro preparation of retinal pigment and scleraltissue and measuring the effect of the substance on the composition ofthe proteoglycanes and/or the collagen specific amino acid present inthe tissue culture.
 23. The method according to claim 20 comprisingadding the substance to a tissue culture comprising fibroblasts andidentifying the effect on the composition of the proteoglycanes and/orthe collagen specific amino acid produced by the fibroblasts.
 24. Themethod according to any of claims 20-23 wherein the substance increasesthe content of proteglycanes of the sclera compared to the initialvalue.
 25. The method according to claims 22-24 wherein the substanceseffective of inhibiting the longtitudinal growth of the eye
 26. Themethod according to claim 25 for identifying substances for thetreatment of myopia.
 27. The method according to any of claims 20-23wherein the substance decreases the content of proteglycanes of thesclera, in the tissue culture or in the in vitro preparation,respectively.
 28. The method according to claim 27 for identifyingsubstances effective of increasing the longtitudinal growth of the eye.29. The method according to claim 28 for identifying substances for thetreatment of hypermetropia.
 30. The method according to any of claims21-29 wherein the effect of the substance is detectable within a periodfrom about 1 week to about 12 weeks from the start of the treatment. 31.The method according to any of claims 21-30 wherein the animal is amammal, the tissue culture or the in vitro preparation is derived froman mammal, respectively.
 32. The miethod according to any of thepreceeding claims wherein the substance is selected from the groupconsisting of prostaglandine and analogues thereof; and compounds of thegeneral formula I, II or III

wherein R¹, R³, R⁷, and R⁹ are independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₂₀-alkyl, optionallysubstituted C₂₋₂₀-alkenyl, optionally substituted C₄₋₂₀-alkadienyl,optionally substituted C₆₋₂₀-alkatrienyl, optionally substitutedC₂₋₂₀-alkynyl, optionally substituted C₁₋₂₀-alkoxycarbonyl, optionallysubstituted C₁₋₂₀-alkylcarbonyl, formyl, optionally substituted aryl,optionally substituted aryloxycarbbnyl, optionally substitutedarylcarbonyl, optionally substituted heteroaryl, optionally substitutedheteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl,carbamoyl, mono- and di(C₁₋₂₀-alkyl)aminocarbonyl, mono- anddi(C₁₋₂₀-alkyl)amino-C₁₋₂₀-alkyl-aminocarbonyl, and halogen such asfluoro, chloro, bromo or iodo, and R⁸ is selected from the groupconsisting of hydrogen, optionally substituted C₁₋₂₀-alkyl, optionallysubstituted C₂₋₂₀-alkenyl, optionally substituted C₄₋₂₀-alkadienyloptionally substituted C₆₋₂₀-alkatrienyl, optionally substitutedC₂₋₂₀-alkynyl, optionally substituted C₁₋₂₀-alkoxy, optionallysubstituted C₂₋₂₀-alkenyloxy, carboxy, hydroxy, optionally substitutedC₁₋₂₀-alkoxycarbonyl, optionally substituted C₁₋₂₀-alkylcarbonyl,formyl, optionally substituted aryl, optionally substitutedaryloxycarbonyl, optionally substituted aryloxy, optionally substitutedarylcarbonyl, optionally substituted arylcarbonyl, optionallysubstituted heteroaryl, optionally substituted heteroaryloxycarbonyl,optionally substituted heteroaryloxy, optionally substitutedheteroarylcarbonyl, amino, mono- and di(C₁₋₂₀-alkyl)amino, carbamoyl,mono- and di(C₁₋₂₀-alkyl)aminocarbonyl, amino-C₁₋₂₀-aminocarbonyl, mono-and di(C₁₋₂₀-alkyl)amino-C₁₋₂₀-alkylaminocarbonyl, optionallysubstituted C₁₋₂₀-alkylcarbonylamino, guanidino, carbamido, optionallysubstituted C₁₋₂₀-alkanoyloxy, sulphono, optionally substitutedC₁₋₂₀-alkylsulphonyloxy, nitro, sulphanyl, optionally substituted C₁₂₀-alkylthio, and halogen such as fluoro, chloro, bromo or iodo. 33.Method according to claim 32, wherein R¹, R³, R⁷, and R⁹ areindependently selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl,optionally-substituted C₂₋₆-alkynyl, optionally substitutedC₁₋₆-alkylcarbonyl, formyl, optionally substituted aryl, optionallysubstituted arylcarbonyl, optionally substituted heteroaryl, andoptionally substituted hetetoarylcarbonyl, and R⁸ is selected from thegroup consisting of hydrogen, optionally substituted C₁₋₆-alkyl,optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₂₋₆alkenyloxy, carboxy, hydroxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,optionally substituted aryl, optionally substituted aryloxycarbonyl,optionally substituted aryloxy, optionally substituted aryicarbonyl,optionally substituted arylcarbonyl, optionally substituted heteroaryl,optionally substituted heteroaryloxycarbonyl, optionally substitutedheteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, optionally substitutedC₁₋₆-alkylcarbonylamino, guanidino, carbamido, optionally substitutedC₁₋₆-alkanoylpxy, sulphono, optionally substitutedC₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, optionally substitutedC₁₋₆-alkylthio, and halogen such as fluoro, chloro, bromo or iodo. 34.The method according to claim 33, wherein R¹, R³, R⁷ and R⁹ areindependently selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionallysubstituted C₂₋₆-alkynyl, optionally substituted aryl, and R⁸ isselected from the group consisting of hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₂₋₆alkenyloxy, carboxy, hydroxy, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylcarbonyl, amino, nitro, sulphanyl, and halogen such as fluoro,chloro, bromo or iodo.
 35. Use of a substance having an effect on theretinal pigment epithelium identified according to the method describedin any of the claims 1-34 for the preparation of a medicament fortreating or preventing disorders of the eye related to the axial lengthof the eye.
 36. Use according to claim 35 for the preparation of amedicament for topical application in the form of a preparation suitablefor application on mucosa e.g. for application on eye mucosa e.g. eyedrops, eye salve, eye gel, or an eye insert; or for application on nasalmucosa e.g. a nasal insert, a nasal drop or spray, a nasal ointment orgel.
 37. Use according to claim 36 for the preparation of a medicamentfor topical application in the form of a powder, paste, ointment,lotion, gel, cream, emulsion, solution, suspension, spray, sponge,strip, plaster, pad, or dressing; or for the preparation of a medicamentfor implantation.
 38. Use according to claim 35 for the preparation of amedicament for injection or systemic administration, characterized inthat the medicament is in a form suitable for injection or systemicadministration, e.g. a solution or a suspension.
 39. Use according toany of claims 35-38 wherein the concentration of the substance ormixture of substances is present in the medicament in an amount of0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-10%by weight of the medicament.
 40. Method for treating or preventingdisorders of the eye related to the axial length of the eye comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of one or more substances selected from the group ofcompounds of the general formula I, II or III

wherein R¹, R³, R⁷, and R⁹ are independently selected from the groupconsisting of hydrogen, optionnally substituted C₁₋₂₀-alkyl, optionallysubstituted C₂₋₂₀-alkenyl, optionally substituted C₄₋₂₀-alkadienyl,optionally substituted c₆₋₂₀-alkatrienyl, optionally substitutedC₂₋₂₀-alkynyl, optionally substituted C₁₋₂₀-alkoxycarbonyl, optionallysubstituted C₁₋₂₀-alkylcarbonyl, formyl, optionally substituted aryl,optionally substituted aryloxycarbonyl, optionally substitutedarylcarbonyl, optionally substituted heteroaryl, optionally substitutedheteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl,carbamoyl, mono- and di(C₁₋₂₀-alkyl)aminocarbonyl, mono- anddi(C₁₋₂₀-alkyl)amino-C₁₋₂₀-alkyl-aminotarbonyl, and halogen such asfluoro, chloro, bromo or iodo, and R⁸ is selected from the groupconsisting of hydrogen, optionally substituted C₁₋₂₀-alkyl, optionallysubstituted C₂₋₂₀-alkenyl, optionally substituted C₄₋₂₀-alkadienyl,optionally substituted C₆₋₂₀-alkatrienyl, optionally substitutedC₂₋₂₀-alkynyl, optionally substituted C₁₋₂₀-alkoxy, optionallysubstituted C₂₋₂₀-alkenyloxy, carboxy, hydroxy, optionally substitutedC₁₋₂₀-alkoxycarbonyl, optionally substituted C₁₋₂₀-alkylcarbonyl,formyl, optionally substituted aryl, optionally substitutedaryloxycarbonyl, optionally substituted aryloxy, optionally substitutedarylcarbonyl, optionally substituted arylcarbonyl, optionallysubstituted heteroaryl, optionally substituted heteroaryloxycarbonyl,optionally substituted heteroaryloxy, optionally substitutedheteroarylcarbonyl, amino, mono- and di(C₁₋₂₀-alkyl)amino, carbamoyl,mono- and di(C₁₋₂₀-alkyl)aminocarbonyl, amino-C₁₋₂₀-alkylaminocarbonyl,mono- and di(C₁₋₂₀-alkyl)amino-C₁₋₂₀-alkylaminocarbonyl, optionallysubstituted C₁₋₂₀-alkylcarbonylamino, guanidino, carbamido, optionallysubstituted C₁₋₂₀-alkanoyloxy, sulphono, optionally substitutedC₁₋₂₀-alkylsulphonyloxy, nitro, sulphanyl, optionally substitutedC₁₋₂₀-alkylthio, and halogen such as fluoro, chloro, bromo or iodo. 41.Method according to claim 40, wherein R¹, R³, R⁷, and R⁹ areindependently selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionallysubstituted C₂₋₆-alkynyl, optionally substituted C₁₋₆-alkylcarbonyl,formyl, optionally substituted aryl, optionally substitutedarylcarbonyl, optionally substituted heteroaryl, and optionallysubstituted hetergarylcarbonyl, and R⁸ is selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆-alkyl, optionallysubstituted C₂₋₆-alkenyl, optionally substituted C₂₋₆-alkynyl,optionally substituted C₁₋₆-alkoxy, optionally substitutedC₂₋₆-alkenyloxy, carboxy, hydroxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,optionally substituted aryl, optionally substituted aryloxycarbonyl,optionally substituted aryloxy, optionally substituted arylcarbonyl,optionally substituted arylcarbonyl, optionally substituted heteroaryl,optionally substituted helteroaryloxycarbonyl, optionally substitutedheteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, optionally substitutedC₁₋₆-alkylcarbonylamino, guanidino, carbamido, optionally substitutedC₁₋₆-alkanoyloxy, sulphono, optionally substitutedC₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, optionally substitutedC₁₋₆-alkylthio, and halogen such as fluoro, chloro, bromo or iodo. 42.The method according to claim 41, wherein R¹, R³, R⁷ and R⁹ areindependently selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionallysubstituted C₂₋₆-alkynyl, optionally substituted aryl, and R⁸ isselected from the group consisting of hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₂₋₆-alkenyloxy, carboxy, hydroxy, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedhetero-arylcarbonyl, amino, nitro, sulphanyl, and halogen such asfluoro, chloro, bromo or iodo.
 43. Method for treating and/or preventingmyopia of a human eye comprising administering to an individual in needthereof a therapeutically effective amount of one or more substancesselected from caffeine; 1,7-dimethylxanthine (paraxanthine),7-methylxanthine (heteroxanthine), 3-methylxanthine; 1-methylxanthine,isobutylmethylxanthine (IBMX) and derivatives;1-Hexyl-3,7-dimethylxanthine (pentifylline); 1,7-Dimethyl-xanthine;1,3-Dipropyl-7-methyl-xanthine; 7-Propylxanthine;7β-Chloroethyl-1,3-dimethylxanthine; 3,7-Dimethyl-1-propargyl-xanthine;3-Propylxanthine; 1-(5-Oxohexyl)-3,7-dimethylxanthine (pentoxyfylline);3-Isobutyl-1-methylxanthine; 3,9-Dimethylxanthine8-Cyclopentyl-1,3-dimethylxanthine;1,3-Bis(3-methylbut-2-butenyl-7-methylxanthine;3,7-Dihydro-7-methyl-1,3-dipropyl-1H-purine-2,6-dione;7-Methyl-1,3-diprenylxanthine(7-methyl-1,3-dipropyl-xanthine;7-Ethoxymethyl-1-(5-hydroxy-5-methylhex-methylxanthine (Torbafylline,“HWA 448”); 1-(5 hydoxy-5-methylhexyl)-3-methyl-7-propylxanthine (A80.2715); 3,7-Dimethyl-1-(5-oxyhexyl)-xanthine (Pentoxifylline,“Trental”); 3,7-Dimethyl-1-(5-hydroxyhexyl)-xanthine(Hydroxypentoxifylline); 1-Hexyl-3,7-dimethylxanthine (Pentifylline,“Cosaldon”); 3,7-Dimethyl-1-proparglyxanthine (DMPX);(E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837)(Lisofylline); 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine(Albifylline, “HWA 138”): 3-Methyl-1-(5′-oxohexyl)-7-propylxanthine(Propeptofylline, “HWA 285”); 1-(5-Hydroxyhexyl)-3,7-dimethylxanthine(BL 194); (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KF17.837); 1,3-di-n-butyl-7-(2′oxopropyl)-xanthine (Denbufylline);1-n-butyl-3-n-propylxanthine (XT-044);7-(2,3-dihydroxypropyl)-theophylline (Dyphylline);7-Methyl-8-(2-hydroxy-N-methylethylamino)-theophylline (Cafaminol);7-(1,3-Dioxolan 2-ylmethyl)-theophylline (Doxofylline);7-(2-Hydroxyethyl)-1,3-dimethylxanthine (Etofylline);7-(2-Hydroxypropyl)-1,3-dimethylxanthine (Proxyphylline);Pyridoxine-O-(theophyllin-7-ylethyl)sulphate (Pyridofylline);7-(2-(3-diethylcarbamoylpropionyloxy)ethyl)theophylline(Suxamidofylline); Piperazine bis(theophyllin-7-ylacetate)(Acepifylline);8-benzyl-7-(2-(N-ethyl-N-2-hydroxyethylamino)ethyl)theophylline(Bamifylline); 2-amino-2-methylpropan-1-ol theophyllinate (Bufylline);7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine (Diprophylline);7-(2-diethylamoinoethyl)-1,3-dimethylxanthine camphor 10 sulphonate(Etamiphylline Camsylate); 3-Propylxanthine (Enprofylline);4-amino-8-chloro-1-phenyl-(1,2,4)-triazolo (4,3-a)quinoxaline (CP71366); cysteine/cystine; glycine; forskoline; alpha-2-adrenergicagonist such as brimonidine (UK-14,304), clonidine, apraclonidine,dapiprazole, moxonidine(4-chloro-N-(4,5dihydro-1H-imidasol-2yl)-6-methoxy-2-methyl-5-pyridinamine),medetomidine, oxymetazoline, or derivatives thereof; peptides such asbradykinin, arginine vasopressin including V2 agonists, bombesine,substance P, pituitary adenylate cyclase activating polypeptide;somatostatftin analogues: such as tyril-somatostatin-14, Leu8,D-Trp22,and Tyr25-somatostatin-28 including agonists of somatostatin sst2receptors, neuropeptide Y including agonists of Y2 receptors, andanlogues of these peptides; calcitriol or analogues of calcitriol orVitamin D; muscarine receptor agonists such as the Carbachol,acetylincholine or analogues thereof; nonsteroidal anti-inflammatorydrugs such as niflumic acid; prostaglandine and analogues thereof suchas F2-alpha analogues inciuding PhXA41 (latanoprost), prostaglandinreceptor agonists including PGF 2 alpha, 17-phenyl trinor PGE2, andU46619 FP, EP1, and TP receptor agonists), UF 021, 16-phenoxy-PGF2alpha, cloprostenol, 17-phenyl-PGF2 alpha, fluprostenol, and PhXA85;Thapsigargin, A23187, Phosphodiesterase inhibitors including rolipramand Zaprinast, 4-chloro-3-ethylphenol and Bastidin, veratridine,esterogens including analogues thereof; Bay K 8644(1,4-Dihydro-2,6-dimethyl-5-nitor-4-(2(triflouromethyl)-phenyl)-3-pyridinencarboxylicacid methyl ester; angiotensin converting enzyme inhibitors, inparticular captopril (SQ 14225); adenosine A2-receptor agonists such as5(N-ethyl)-.carboxamido adenosine -and-8-phenylaminoadenosine (CV-1808);Candoxatril (neutral endopeptidase 24.11 (NEP) inhibitor)Met-enkephalin, alphaendorphin or derivatives; and mixtures thereof. 44.The method for treating or preventing myopia according to claim 43comprising a mixture of two or more substances having a synergisticeffect on the myopia.
 45. The method for treating or preventing myopiaaccording to any of claims 43 and 44 comprising caffeine or derivativethereof wherein the caffeine or the derivative thereof is administeredin a dosage of 7.5-750 mg 1-4 times daily.
 46. The method for treatingor preventing myopia according to any of claims 43-44 comprisingcystein/cystin wherein the cystein/cystin is administered in a dosage of20-2000 mg 1-4 times daily.
 47. The method for treating or preventingmyopia according to any of claims 43-44 comprising forskoline whereinthe forskoline is administered in a dosage of 5-560 mg 1-4 times daily.48. Method for treating and/or preventing hypermetropia of a human eyecomprising administering to an individual in need thereof atherapeutically effective amounts of one or more substances selectedfrom-theophylline; 3,7-dimethylxanthine (theobromine), xanthine;1,9-dimethylxanthine; 1,3-Dipropyl-8-(2-(5,6-epoxynorbonyl)-xanthine;8-Cyclopentyl-l,3-dipropylxanthine (CPDPX); 8-Sulphophenyltheophylline;1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433);(1-Propyl-11C)8-dicyclopropylmethyl-1,3-dipropylxanthine (11C)KFP15372and 11C-ethyl and 11C-methyl derivatives thereof; 8-Benzyl-7,(2-(ethyl(2-hydroxyethyl)amino)ethyl)theo-phylline (Bamiphylline);8-Cyclopentyl-3-(3-((4-(flourosulfonyl)benzoyl)oxyl)pro-pyl)-1-propylxanthine;1,3-Dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyl-oxyphenyl)xanthine;8-(3-chlorostyryl)caffeine; 8-cyclopentyltheophylline; 8-(noradamantan-3yl)-1,3-dipropylxanthine (KW-3902);1,3-Dipropyl-8-(3-noradamantyl)-xanthine;1,3-Dipropyl-8-(4-sulphpphenyl)-xanthine;1,3-Dipropyl-8-(2-amino-4-chlorophenyl)-xanthine;7β-Hydroxyethyl-1,3-dimethylxanthine;7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine;8-Chloro-1,3-dimethylxanthine; 1,3,9-Trimethylxanthine; 8-Propionicacid-1,3-dimethylxanthine; 7,9-Dimethylxanthine;8-Phenyl-1,3-dimethylxanthine; 7-Acetic acid-1,3-dimethylxanthine;9-Propylxantine; 9-Methlxanthne; 8-Methylxanthine;8-(p-Sulfophenyl)-1,3-dimethylxanthine; 1,9-Dimethylxanthine;hypoxanthine; ethylendiamin; fluoxetine; L-ornithine; azetazolamid;bumetanide; Tamoxifen and other estrogen antagonists, the calmodulinantagonist J8, calcium antagonists including nimodipine and nicardipine,Endothelin agonist, in particular sarafotoxin S6c (selective ETBreceptor agonist); Dorzolamide (MK-507), sezolamide and MK-927(thienothiopyran-2-sulfonamide derivatives carbonic anhydraseinhibitors), methazolamide, ethoxzolamide, leuenkephalin or dervatives;and mixtures thereof.
 49. Method according to claim 48 comprising amixture of two or more substances having a synergistic effect on thehypermetropia.
 50. The method for treating or preventing hypermetropiaaccording to any of claims 48-49 comprising L-orhinthine wherein theL-ornithine is administered in a dosage of 20-2000 mg 1-4 times daily.51. The method for treating or preventing hypermetropia according any ofclaims 48-49 comprising fluoxetin wherein the fluoxetin is administeredin a dosage of 0.1-20 mg 1-4 times daily.
 52. The method for treating orpreventing hypermetropia according any of claim 43-46 comprisingazetozolamid wherein the azetazolamid is administered in a dosage of5-500 mg 1-4 times daily.
 53. The method for treating or preventinghypermetropia according to any of claims 48-52 wherein theophyllineand/or the 3-methylxanthin and/or 1-methylxanthine and/or xanthineis/are administered in a dosage of 7.5-750 mg 1-4 times daily.
 54. Amethod according to any of the preceeding claims wherein the substanceis administered systemically.
 55. Pharmaceutical preparation fortreating and/or preventing myopia of a human eye comprising atherapeutically effective amount of one or more substances selected fromcaffeine; 1,7-dimethylxanthine (paraxanthine), 7-methylxanthine(heteroxanthine) isobutylmethylxanthine (IBMX) and derivatives;3-methylxanthine, 1-methylxanthine; 1-Hexyl3,7-dimethylxanthine(pentifylline); 1,7-Dimethyl-xanthine; 1,3-Dipropyl7-methyl-xanthine;7-Propylxanthine; 7β-Chloroethyl-1,3-dimethylxanthine; C3,7-Dimethyl-1-propargyl-xanthine, 3-Propylxanthine;1-(5-Oxohexyl)-3,7-dimethylxanthine (pentoxyfylline);3-Isobutyl-1-methylxanthine; 3,9-Dimethylxanthine8-Cyclopentyl-1,3-dimethylxanthine;1,3-Bis(3-methylbut-2-butenyl-7-methylxanthine;3,7-Dihydro-7-methyl-1,3-dipropyl-1H-purine-2,6-dione;7-Methyl-1,3-diprenylxanthine(7-methyl-1,3-dipropyl-xanthine;7-Ethoxymethyl-1-(5-hydroxy-5-methylhex-methylxanthine (Torbafylline,“HWA 448”); 1-(5 hydoxy-5-methylhexyl)-3-methyl-7-propylxanthine (A80.2715); 3,7-Dimethyl-1-(5-oxyhexyl)-xanthine (Pentoxifylline, “Trental”); 3,7-Dimethyl-1-(5-hydroxyhexyl)-xanthine (Hydroxypentoxifylline);1-Hexyl-3,7-dimethylxanthine (Pentifylline, “Cosaldon”);3,7-Dimethyl-1-proparglyxanthine (DMPX);(E)-8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837)(Lisofylline); 1-(5-Hydroxy-5-methylhexyl)-3-methylxanthine(Albifylline, “HWA 138”): 3-Methyl-1-(5′-oxohexyl)-7-propylxanthine(Propentefylline, “HWA 285”); 1-(5-Hydroxyhexyl)-3,7-dimethylxanthine(BL 194); (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KF17.837); 1,3-di-n-butyl-7-(2′oxopropyl)-xanthine (Denbufylline);1-n-butyl-3-n-propylxanthine (XT-044);7-(2,3-dihydroxypropyl)-theophylline (Dyphylline);7-Methyl-8-(2-hydroxy-N-!methylethylamino)-theophylline (Cafaminol);7-(1,3-Dioxolan 2-ylmethyl)-theophylline (Doxofylline);7-(2-Hydroxyethyl)-1,3-dimethylxanthine (Etofylline);7-(2-Hydroxypropyl)-1,3-dimethylxanthine-(Pyoxypylline);Pyridoxine-O-(theophyllin-7-ylethyl)sulphate (Pyridofylline);7-(2-(3-diethylcarbamoylpropionyloxy)ethyl)theophylline(Suxamidofylline); Piperazine bis(theophyllin-7-ylacetate)(Acepifylline);8-benzyl-7-(2-(N-ethyl-N-2-hydroxyethylamino)ethyl)theophylline(Bamifylline); 2-amino-2-methylpropan-1-ol theophyllninate (Bufylline);7-(2,3-Dihydroxypropyl)-1,3-dimethylxanthine (Diprophylline);7-(2-diethylamoinoethyl)-1,3-dimethylxanthine camphor 10 sulphonate(Etamiphylline Camsylate); 3-Propylxanthine (Enprofylline);4-amino-8-chloro-1-phenyl-(1,2,4)-triazolo (4,3-a)quinoxaline (CP71366); cysteine/cystine; glycine; forskoline; alpha-2-adrenergicagonist such as brimonidine (UK-14,304), clonidine, apraclonidine,dapiprazole, moxonidine (4-chloro-N-(4,5dihydro-1H-imidasol-2yl)-6-methoxy-2-methyl-5-pyridinamine),medetomidine, oxymetazoline, or derivatives thereof; peptides such asbradykinin, arginine vasopressin including V2 agonists, bombesine,substance P, pituitary adenylate cyclase activating polypeptide;somatostatin analogues such as Tyril-somatostatin-14, Leu8,D-Trp22, andTyr25-somatostatin-28 including agonists of somatostatin sst2 receptors,neuropeptide Y including agonists of Y2 receptors, and anlogues of thesepeptides; calcitriol or analogues of calcitriol or Vitamin D; muscarinereceptor agonists such asgthe Carbachol, acetylincholine or analoguesthereof; nonsteroidal anti-inflamtmatory drugs such as niflumic acid;prostaglandine and analogues thereof such as F2 alpha analoguesincluding PhXA41 (latanoprost), prostaglandin receptor agonistsincluding PGF 2 alpha, 17-phenyl trinor PGE2, and U46619 FP, EP1, and TPreceptor agonists), UF 021, 16-phenoxy-PGF2 alpha, cloprostenol,17-phenyl-PGF2 alpha, fluprostenol, and PhXA85; Thapsigargin, A23187,Phosphodiesterase inhibitors including rolipram and Zaprinast,4-chloro-3-ethylphenol and Bastidin, veratridine, esterogens includinganalogues thereof; Bay K 8644(1,4-Dihydro-2,6-dimethyl-5-nitor-4-(2(triflouromethyl)-,Phenyl)-3-pyridinencarboxyllcacid methyl ester; angiotensin converting enzyme inhibitors, inparticular captopril (SQ 14225); adenosine A2-receptor agonists such as5′(N-ethyl)-carboxamido adenosine and 8-pheniylaminoadenosine (CV-1808);Candoxatril (neutral endopeptidase 24.11 (NEP) inhibitor);Met-enkephalin, alphaendorphin or derivatives; and mixtures thereof. andmixtures thereof together with a pharmaceutically acceptable carrier orexcipient.
 56. Pharmaceutical preparation for treating and/or preventinghypermetropia of a human eye comprising a therapeutically effectiveamount of one or more substances selected from theophylline;3,7-dimethylxanthine (theobromine); xanthine; 1,9-dimethylxanthine;1,3-Dipropyl-8-(2-(5,6-epoxynorbonyl)-xanthine;8-Cydlopentyl-1,3-dipropylxanthinle (CPDPX); 8-Sulphophenyltheophylline;1,3-Dipropyl-8-(4-acrylate)phenylxanthine (BW-A1433); (1-Propyl-11C)8-dicyclopropylmethyl-1,3-dipropylxanthine (11C)KF15372 and 11C-ethyland 11C-methyl derivatives thereof;8-Benzyl-7,(2-(ethyl(2-hydroxyethyl)amino)ethyl)theo-phylline(Bamiphylline);8-Cyclopentyl-3-(3-((4-(flourosulfonyl)benzoyl)oxyl)pro-pyl)-1-propylxanthine;1,3-Dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyl-oxyphenyl)xanthine;8-(3-chlorostyryl)caffeine; 8-cyclopentyltheophylline; 8-(noradamantan-3yl)-1,3-dipropylxanthine (KW-3902);1,3-Dipropyl-8-(3-noradamantyl)-xanthine;1,3-Dipropyl-8-(4-sulphophenyl)-xanthine;1,3-Dipropyl-8-(2-amino-4-chlorophenyl)-xanthine; ethylendiamin;xanthine; hypoxanthine; fluoxetine; L-ornithine; azetazolamid;bumetanide; Tamoxifen and other estrogen antagonists, the calmodulinantagonist J8, calcium antagonists including nimodipine and nicadipine,Endothelin agonist, in particular sarafotoxin S6c (selective -ETBreceptor agonist); Dorzolamide (MK-507), sezolamide and MK-927(thienothiopyran-2-sulfonamide derivatives carbonic anhydraseinhibitors), methazolamide, ethoxzolamide, leuenkephalin or dervatives;and mixtures thereof together with a pharmaceutically acceptable carrieror excipient.
 57. Pharmaceutical preparation according to any of claims55 and 56 in the form suitable for application on mucosa e.g. forapplication on eye mucosa e.g. eye drops, eye salve, eye gel, or an eyeinsert; or for application on nasal mucosa e.g. a nasal insert, a nasaldrop-or spray, a nasal ointment or gel.
 58. Pharmaceutical preparationaccording to any of claims 55 and 56 in the form suitable for topicalapplication on skin e.g. a powder, paste, ointment, lotion, gel, cream,emulsion, solution, suspension, spray, sponge, strip, plaster, pad, ordressing.
 59. Pharmaceutical preparation according to any of claims 55and 56 in a form suitable for implantation, injection or systemicadministration.
 60. Pharmaceutical preparation according to any ofclaims 55 and 56 in a form suitable for injection or systemicadministration, e.g. a solution or a suspension.
 61. Pharmaceuticalpreparation according to any of claims 55-60 wherein the concentrationof the substance or the mixture of substances is present in themedicament in an amount of 0.001-99%, typically 0.01-75%, more typically0.1-20%, especially 1-10% by weight of the medicament. 62.Pharmaceutical preparation according to any of claims 55-61 wherein thesubstance or the mixture of substance are extracted from naturalsources.
 63. Use of a compound of the general formula I, II or III

wherein R¹, R³, R⁷, and R⁹ are independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₂₀-alkyl, optionallysubstituted C₂₋₂₀-alkenyl, optionally substituted C₄₋₂₀-alkadienyl,optionally substituted C₆₋₂₀, alkatrienyl, optionally substituted C₂₋₂₀alkynyl, optionally substituted C₁₋₂₀-alkcxycarbonyl, optionallysubstituted C₁₋₂₀-alkylcarbonyl, formyl, optionally substituted aryl,optionally substituted aryloxycarbonyl, optionally substitutedarylcarbonyl, optionallysubstituted he teroaryl, optionally substitutedheteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl,carbamoyl, mono- and di(C₁₋₂₀-alkyl)aminocarbonyl, mono- anddi(C₁₋₂₀-alkyl)amino-C₁₋₂₀-alkyl-aminocarbonyl, and halogen such asfluoro, chloro, bromo or iodo, and R⁸ is selected from the groupconsisting of hydrogen, optionally substituted C₁₋₂₀-alkyl, optionallysubstituted C₂₋₂₀-alkenyl, optionally substituted C₄₋₂₀-alkadienyl,optionally substituted C₆₋₂₀-alkatrienyl, optionally substitutedC₂₋₂₀-alkynyl, optionally substituted C₁₋₂₀-alkoxy, optionallysubstituted C₂₋₂₀-alkenyloxy, carboxy, hydroxy, optionally substitutedC₁₋₂₀-alkoxycarbonyl, optionally substituted C₂₋₂₀-alkylcarbonyl,formyl, optionally substituted aryl, optionally substitutedaryloxycarbonyl, optionally substituted aryloxy, optionally substitutedarylcarbonyl, optionally substituted arylcarbonyl, optionallysubstituted heteroaryl, optionally substituted heteroaryloxycarbonyl,optionally substituted heteroaryloxy, optionally substitutedheteroarylcarbonyl, amino, mono- and di(C₁₋₂₀-alkyl)amino, carbamoyl,mono- and di(C₁₋₂₀-alkyl)aminocarbonyl, amino-C₁₋₂₀-alkylaminocarbonyl,mono- and di(C₁₋₂₀-alkyl)amino-C₁₋₂₀-alkylaminocarbonyl, optionallysubstituted C₁₋₂₀-alkylcarbonylamino, guanidino, carbamido, optionallysubstituted C₁₋₂₀-alkanoyloxy, sulphono, optionally substitutedC₁₋₂₀-alkylsulphonyloxy, nitro, sulphanyl, optionally substitutedC₁₋₂₀-alkylthio, and halogen such as fluoro, chloro, bromo or iodo forthe preparation of a medicament for treating or preventing disorders ofthe eye related to the axial length of the eye.
 64. Use according toclaim 63, wherein R¹, R³, R⁷, and R⁹ are independently selected from thegroup consisting of hydrogen, optionally substituted C₁₋₆-alkyl,optionally substituted C₂₋₆-alkenyl, optionally substituted C₂₋₆alkynyl,optionally substituted C₁₋₆-alkylcarbonyl, formyl, optionallysubstituted aryl, optionally substituted arylcarbonyl, optionallysubstituted heteroaryl, and optionally substituted heteroarylcarbonyl,and R⁸ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionallysubstituted C₂₋₆-alkynyl, optionally substituted C₁₋₆-alkoxy, optionallysubstituted C₂₋₆-alkenyloxy, carboxy, hydroxy, optionally substitutedC₁₋₆-alkoxycarbonyl, optionally substituted C₁₋₆-alkylcarbonyl, formyl,optionally substituted aryl, optionally substituted aryloxycarbonyl,optionally substituted aryloxy, optionally substituted arylcarbonyl,optionally substituted arylcarbonyl, optionally substituted heteroaryl,optionally substituted heteroaryloxycarbonyl, optionally substitutedheteroaryloxy, optionally substituted heteroarylcarbonyl, amino, mono-and di(C₁₋₆-alkyl)amino, carbamoyl, mono- anddi(C₁₋₆-alkyl)amninocarbonyl, optionally substitutedC₁₋₆-alkylcarbonylamino, guanidino, carbamido, optionally substitutedC₁₋₆-alkanoyloxy, sulphono, optionally substitutedC₁₋₆-alkylsulphonyloxy, nitro, sulphanyl, optionally substitutedC₁₋₆-alkylthio, and halogen such as fluoro, chloro, bromo or iodo. 65.Use according to claim 64, wherein R¹, R³, R⁷ and R⁹ are independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆-alkyl, optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted aryl, and R⁸ is selected from thegroup consisting of hydrogen, optionally substituted C₁₋₆-alkyl,optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted C₁₋₆-alkoxy, optionally substitutedC₂₋₆-alkenyloxy, carboxy, hydroxy, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylcarbonyl, amino, nitro, sulphanyl, and halogen such as fluoro,chloro, bromo or iodo.
 66. Use according to any of claims 63-65 whereinthe preparation is in the form suitable for application on mucosa e.g.for application on eye mucosa e.g. eye drops, eye salve, eye gel, or aneye insert; or for application on nasal mucosa e.g. a nasal insert, anasal drop or spray, a nasal ointment or gel.
 67. Use according to anyof claims 63-65 wherein the preparation is in the form suitable fortopical application on skin e.g. a powder, paste, ointment, lotion, gel,cream, emulsion, solution, suspension, spray, sponge, strip, plaster,pad, or dressing.
 68. Use according to any of claims 63-65 wherein thepreparation is in a form suitable for implantation, injection orsystemic administration.
 69. Use according to any of claims 63-68wherein the substance or the mixture of substances is present in themedicament in an amount of 0.001-99%, typically 0.01-75%, more typically0.1-20%, especially 1-10% by weight of the medicament.
 70. Use accordingto any of claims 63-68 wherein the xanthine or substituted xanthine ispresent in a dosage of 7.5-750 mg and is administered 1-4 times daily.71. Use according to any of claims 63-70 excluding an implantat of claim68 wherein the medicament is intended for administration 1-4 timesdaily.
 72. Use-according to any of claims 63-71 wherein the substance orthe mixture of substances are extracted from natural sources.